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  • 351.
    Thornell, Lars-Eric
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Gustafsson, Thomas
    Karolinska Institutet Karolinska University Hospital .
    Cederholm, Tommy
    Department of Public Health and Caring Uppsala Science Park Uppsala.
    Ulfhake, Brun
    Karolinska Institutet .
    "Sarcopenia" has earned its living2012In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 113, no 4, p. 683-684Article in journal (Refereed)
  • 352.
    Thornell, Lars-Eric
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kadi, Fawsi
    Linköping University.
    Lindman, Rolf
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Morphological features related to muscle pain and muscle overload2003In: Chronic work-related Myalgia: Neuromuscular mechanisms behind work-related chronic muscle pain syndromes / [ed] Johansson H, Windhorst U, Djupsjöbacka and M, Passatore M, Gävle: Gävle University Press , 2003, p. 95-109Chapter in book (Other academic)
  • 353.
    Thornell, Lars-Eric
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Lindström, Mona
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Renault, V
    Mouly, V
    Butler-Browne, G S
    Satellite cells and training in the elderly.2003In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 13, no 1, p. 48-55Article in journal (Refereed)
    Abstract [en]

    In the present review, we describe the effects of ageing on human muscle fibres, underlining that each human muscle is unique, meaning that the phenotype becomes specifically changed upon ageing in different muscles, and that the satellite cells are key cells in the regeneration and growth of muscle fibres. Satellite cells are closely associated with muscle fibres, located outside the muscle fibre sarcolemma but beneath the basement lamina. They are quiescent cells, which become activated by stimulation, like muscle fibre injury or increased muscle tension, start replicating and are responsible for the repair of injured muscle fibres and the growth of muscle fibres. The degree of replication is governed by the telomeric clock, which is affected upon excessive bouts of degeneration and regeneration as in muscular dystrophies. The telomeric clock, as in dystrophies, does not seem to be a limiting factor in ageing of human muscle. The number of satellite cells, although reduced in number in aged human muscles, has enough number of cell divisions left to ensure repair throughout the human life span. We propose that an active life, with sufficient general muscular activity, should be recommended to reduce the impairment of skeletal muscle function upon ageing.

  • 354.
    Thornell, Lars-Eric
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Lindstöm, Mona
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Renault, Valerie
    Klein, Arnaud
    Mouly, Vincent
    Ansved, Tor
    Butler-Browne, Gillian
    Furling, Denis
    Satellite cell dysfunction contributes to the progressive muscle atrophy in myotonic dystrophy type 12009In: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 35, no 6, p. 529-633Article in journal (Refereed)
    Abstract [en]

    ABSTRACT Aims: Myotonic Dystrophy type 1 (DM1), one of the most common forms of inherited neuromuscular disorders in the adult, is characterized by progressive muscle weakness and wasting leading to distal muscle atrophy whereas proximal muscles of the same patients are spared during the early phase of the disease. In this report, the role of satellite cell dysfunction in the progressive muscular atrophy has been investigated. Methods: Biopsies were obtained from distal and proximal muscles of the same DM1 patients. Histological and immunohistological analyses were carried out and the past regenerative history of the muscle was evaluated. Satellite cell number was quantified in vivo and proliferative capacity was determined in vitro. Results: The size of the CTG expansion was positively correlated with the severity of the symptoms and the degree of muscle histopathology. Marked atrophy associated with typical DM1 features was observed in distal muscles of severely affected patients whereas proximal muscles were relatively spared. The number of satellite cells was significantly increased (2-fold) in the distal muscles whereas very little regeneration was observed as confirmed by telomere analyses and developmental MyHC staining (0,3% to 3%). The satellite cells isolated from the DM1 distal muscles had a reduced proliferative capacity (36%) and stopped growing prematurely with telomeres longer than control cells (8,4kb vs 7,1kb) indicating that the behaviour of these precursor cells was modified. Conclusions: Our results indicate that alterations in the basic functions of the satellite cells progressively impair the muscle mass maintenance and/or regeneration resulting in gradual muscular atrophy.

  • 355. Thornton, Martin R
    et al.
    Shawcross, Susan G
    Mantovani, Cristina
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Birchall, Martin A
    Terenghi, Giorgio
    Neurotrophins 3 and 4 differentially regulate NCAM, L1 and N-cadherin expression during peripheral nerve regeneration.2008In: Biotechnology and applied biochemistry, ISSN 0885-4513, E-ISSN 1470-8744, Vol. 49, no Pt 2, p. 165-74Article in journal (Refereed)
    Abstract [en]

    The addition of NT-3 (neurotrophin 3) or NT-4 to injured nerves improves their regeneration potential and may aid axon guidance. It is not well defined whether NTs (neurotrophins) influence other elements, such as the cell-adhesion molecules, which promote nerve guidance and regeneration. Using poly-3-hydroxybutyrate conduits, we applied either NT-3 or NT-4 to axotomized rat sciatic nerves and monitored nerve regeneration and cell-adhesion molecule expression. Regenerating nerves were stained with antibodies against NCAM (neural cell-adhesion molecule) and N-cadherin 2 weeks after injury and staining intensity was quantified. NCAM, N-cadherin and L1 (L1 cell-adhesion molecule) transcription was measured in the proximal and distal stumps and ipsilateral DRG (dorsal root ganglia) (fourth and fifth DRG) using RT (reverse transcriptase)-PCR. Both NT-3 and NT-4 increased NCAM and L1 transcript levels in the DRG of axotomized nerves. This is reflected in the increased NCAM expression at the proximal stump and regeneration front. Increased levels of NCAM were also observed in the distal stump. NT-4 administration increased N-cadherin levels proximal to the injury, but not distally. Following NT-3 administration, N-cadherin expression decreased in proximal and distal stumps compared with the control. In conclusion, NTs differentially alter adhesion molecule expression in regenerating nerves and transcription in the corresponding DRG, although these changes in expression do not alter NT-enhanced regeneration. Thus we propose that retrograde transport of the NTs to the DRG affects adhesion molecule transcription, reflected by protein expression in peripheral nerve axons.

  • 356. Tingaker, Berith K
    et al.
    Ekman-Ordeberg, Gunvor
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Presence of sensory nerve corpuscles in the human corpus and cervix uteri during pregnancy and labor as revealed by immunohistochemistry.2006In: Reprod Biol Endocrinol, ISSN 1477-7827, Vol. 4, p. 45-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The uterus is exposed to changes such as enlargement and distension during pregnancy and labor. In these processes and in the process of cervical ripening, proprioceptive information is likely to be of great importance. Therefore, we wanted to study the possible existence of sensory nerve corpuscles in uterine corpus and cervix during pregnancy and labor. Studies on this aspect have not previously been perfomed. METHODS: Biopsies were taken from the upper edge of the hysterotomy during caesarean section at term (n = 8), in labor (n = 5) and from the corresponding area in the non-pregnant uterus after hysterectomy (n = 7). Cervical biopsies were obtained transvaginally from the anterior cervical lip. Serial cryostat sections were prepared for immunohistochemistry using polyclonal antibodies against nerve growth factor receptor p75, protein gene product 9.5 and S-100. RESULTS: Structures with the characteristics of sensory nerve corpuscles were observed in several specimens after staining for p75, PGP 9.5 and S-100. They were observed in specimens of the non-pregnant corpus and cervix and also in specimens of the pregnant cervix before onset of labor. However, they were absent in all specimens during labor. CONCLUSION: Sensory corpuscles have here for the first time been detected in the human corpus and cervix uteri. Studies on the importance of the corpuscles in relation to the protective reflex actions that occur in the uterus during pregnancy should be performed in the future.

  • 357.
    Tjust, Anton
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Extraocular Muscles in Amyotrophic Lateral Sclerosis2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease of motor neurons characterized by muscle paralysis and death within 3-5 years of onset. However, due to unknown mechanisms, the extraocular muscles (EOMs) remain remarkably unaffected. The EOMs are highly specialized muscles that differ from other muscles in many respects, including innervation and satellite cells (SCs). Understanding whether these factors play a role in the relative sparing of EOMs in ALS could provide useful clues on how to slow down the progression of ALS in other muscles.

    The EOMs and limb muscles from terminal ALS patients and age-matched controls as well as the commonly used SOD1G93A ALS mouse model were studied with immunofluorescence. Antibodies against neurofilament and synaptophysin were used to identify nerves and neuromuscular junctions (NMJs); against Pax7, NCAM, MyoD, myogenin, Ki-67, dystrophin and laminin, to identify SCs and their progeny in EOMs and limb muscles. The proportion and fiber size of myofibers containing myosin heavy chain (MyHC) slow tonic and MyHC slow twitch were also determined in human EOMs.

    The abundance of SCs differed extensively along the length of control human EOMs, being twice as abundant in the anterior portion. Pax7-positive cells were also detected in non-traditional SC positions. EOMs from terminal ALS patients showed similar numbers of resting and activated SCs as the controls. In limb muscles of ALS patients, the number of resting and activated SCs ranged from low (similar to normal aged, sedentary individuals) to high numbers, especially in muscles with long duration of disease and varied between the upper and lower limbs. The EOMs maintained a high degree of innervation compared to hindlimb muscles of symptomatic SOD1G93A mice. MyHC slow tonic fibers were less abundant in ALS patients than in controls. The change seemed more pronounced in bulbar onset patients, and in this group of subjects only, there was a strong association between decline in MyHC slow tonic fibers and age of death. Notably, the decline in MyHC slow tonic fibers was unrelated to disease duration.

    Our data suggested that SCs play a minor role in the progression of ALS in general and in the sparing of the EOMs in particular. The generally preserved innervation in the EOMs of G93A mice may reflect distinct intrinsic properties relevant for sparing of the oculomotor system.  Even though the EOMs are relatively spared in ALS, MyHC slow tonic myofibers were selectively affected and this may reflect differences in innervation, as these fibers are multiply innervated.

  • 358.
    Tjust, Anton
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Danielsson, Adam
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pedrosa Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Impact of ALS on slow tonic myofiber composition in human extraocular musclesManuscript (preprint) (Other academic)
  • 359.
    Tjust, Anton E
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Brännstrom, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pedrosa Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Unaffected motor endplate occupancy in eye muscles of ALS G93A mouse model2012In: Frontiers in bioscience (Scholar edition), ISSN 1945-0524, Vol. 4, p. 1547-1555Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neurodegenerative disorder characterised by selective loss of motor neurons with accompanying muscle paralysis and respiratory failure. Despite progressive paralysis in trunk and extremity muscles, disturbed eye motility is not a hallmark of ALS. Extraocular muscles (EOMs) of terminal ALS patients show far less morphological signs of disease than their limb muscles. One of the earliest signs of the disease in the transgenic G93A SOD1 mouse model of ALS is loss of motor neuron contact at the neuromuscular junctions (NMJ) in limb muscles. We used immunohistochemistry to identify NMJs and evaluate innervation in EOMs and limb muscles of G93A mice. In G93A limb muscles, loss of axonal contact was seen in 6-82 percent of the NMJs. On the contrary, the degree of endplate occupancy in the EOMs did not differ between transgenic mice and wild-type controls. We propose that EOM-specific properties make these muscles more resistant to the underlying pathophysiological process of ALS and that the EOMs are a useful model to advance our understanding of ALS.

  • 360.
    Tjust, Anton
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Lindström, Mona
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Sjöström, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pedrosa Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Satellite cells and other muscle progenitor cells in extraocular muscles and limb muscles of ALS donorsManuscript (preprint) (Other academic)
  • 361. Tohill, Mel
    et al.
    Mantovani, Cristina
    Blond McIndoe Research Laboratories, University of Manchester, Manchester, UK.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Terenghi, Giorgio
    Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration2004In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 362, no 3, p. 200-203Article in journal (Refereed)
    Abstract [en]

    Bone marrow mesenchymal stem cells can trans-differentiate into neuronal phenotypes. We examined the differentiation of marrow stromal cells (MSCs) in culture and during nerve regeneration. MSCs from adult rats were exposed to glial growth factor (GGF) to stimulate glial differentiation. Subsequently differentiated MSCs were retrovirally labelled with green fluorescent protein and transplanted into 1 cm nerve conduits in the rat sciatic nerve. Fifteen days post-operatively the conduits were examined for axonal and Schwann cell regeneration and MSC integration. In vitro, MSCs exposed to GGF expressed S100 and glial fibrillary acidic protein. Following transplantation, MSCs maintained S100 expression and enhanced nerve regeneration, with significant Schwann cell regeneration compared to control (2.7 +/- 0.21 vs. 2.05 +/- .21 mm; P < 0.05). MSCs not exposed to GGF prior to transplantation expressed S100 in vivo indicating glial differentiation in response to local cytokines and growth factors.

  • 362.
    Tohill, Mel P
    et al.
    Blond McIndoe Research Laboratories, University of Manchester, Manchester, UK.
    Mann, Dawn J
    Blond McIndoe Centre, Queen Victoria Hospital, East Grinstead, UK.
    Mantovani, Cristina M
    Blond McIndoe Research Laboratories, University of Manchester, Manchester, UK.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Terenghi, Giorgio
    Blond McIndoe Centre, Queen Victoria Hospital, East Grinstead, UK.
    Green fluorescent protein is a stable morphological marker for schwann cell transplants in bioengineered nerve conduits2004In: Tissue engineering, ISSN 1076-3279, E-ISSN 1557-8690, Vol. 10, no 9-10, p. 1359-1367Article in journal (Refereed)
    Abstract [en]

    Bioengineered systems incorporate cultured cells to mimic the substituted tissue. A labeling method is necessary to monitor the survival of transplanted cells within the host. This labeling method must be compatible with the histochemical methods used for morphological analysis. This study assessed (1) The in vitro characteristics of Schwann cells (SCs) labeled with green fluorescent protein (GFP), (2) the in vivo effect of transplanted GFP-SCs in a model of peripheral nerve injury, and (3) the compatibility of GFP-SCs with immunofluorescence histochemical techniques. SCs were retrovirally labeled with GFP and their growth characteristics were compared with those of nontransduced SCs (ntSCs). GFP-SCs were seeded in a resorbable nerve conduit for grafting into a 1-cm gap in rat sciatic nerve. Grafts were harvested after 2 weeks and immunofluorescent staining was performed to measure axonal and SC regeneration distances and to identify GFP-SCs. Results of GFP-SC vitality assays did not vary significantly from those of ntSC assays. GFP-SCs were readily located ex vivo and stimulated significantly better axonal and SC regeneration distances in comparison with empty conduits. These findings show that GFP labeling does not have a deleterious effect on SCs and that it is a useful labeling method for the study of bioengineered systems.

  • 363.
    Tremp, Mathias
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Schwabedissen, Moritz Meyer zu
    Kappos, Elisabeth A.
    Engels, Patricia E.
    Fischmann, Arne
    Scherberich, Arnaud
    Schaefer, Dirk J.
    Kalbermatten, Daniel F
    The Regeneration Potential After Human and Autologous Stem Cell Transplantation in a Rat Sciatic Nerve Injury Model Can Be Monitored by MRI2015In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 24, no 2, p. 203-211Article in journal (Refereed)
    Abstract [en]

    Traumatic nerve injuries are a major clinical challenge. Tissue engineering using a combination of nerve conduits and cell-based therapies represents a promising approach to nerve repair. The aim of this study was to examine the regeneration potential of human adipose-derived stem cells (hASCs) after transplantation in a nonautogenous setting and to compare them with autogenous rat ASCs (rASCs) for early peripheral nerve regeneration. Furthermore, the use of MRI to assess the continuous process of nerve regeneration was elaborated. The sciatic nerve injury model in female Sprague Dawley rats was applied, and a 10-mm gap created by using a fibrin conduit seeded with the following cell types: rASCs, Schwann cell (SC)-like cells from rASC, rat SCs (rSCs), hASCs from the superficial and deep abdominal layer, as well as human stomal vascular fraction (1 x 10(6) cells). As a negative control group, culture medium only was used. After 2 weeks, nerve regeneration was assessed by immunocytochemistry. Furthermore, MRI was performed after 2 and 4 weeks to monitor nerve regeneration. Autogenous ASCs and SC-like cells led to accelerated peripheral nerve regeneration, whereas the human stem cell groups displayed inferior results. Nevertheless, positive trends could be observed for hASCs from the deep abdominal layer. By using a clinical 3T MRI scanner, we were able to visualize the graft as a small black outline and small hyperintensity indicating the regenerating axon front. Furthermore, a strong correlation was found between the length of the regenerating axon front measured by MRI and the length measured by immunocytochemistty (r= 0.74, p = 0.09). We successfully transplanted and compared human and autologous stem cells for peripheral nerve regeneration in a rat sciatic nerve injury model. Furthermore, we were able to implement the clinical 3T MRI scanner to monitor the efficacy of cellular therapy over time.

  • 364.
    Tse, Kai-Hei
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Mechanisms and improvements of cell transplantation for nerve repair2011Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Trauma to the nervous system is a frequent clinical problem and new approaches to nerve repair are required. Autologous cell transplantation together with a suitable scaffold material could be used to create a bio-active artificial nerve graft to enhance regeneration. The work presented in this licentiate thesis attempts to improve both the biomaterial and cellular components of this repair strategy.

    In the first study, by using common biodegradable polyesters, namely poly-ε-caprolactone (PCL) and poly -L,D- lactic acid (PLA), a thin film scaffold prototype was fabricated by using a solvent-evaporation method. These scaffolds, with thicknesses of approximately 10-20 µm, exhibited a heterogenous but continuous surface topography decorated with pore/pits of regulated sizes. The sizes of the pore/pits ranged from 0.5 to 30 µm2and could be modulated by varying the ratios of PLA and PCL. Biocompatibility of these scaffolds was demonstrated by using adipose derived stem cells (ADSC) differentiated into a Schwann cell-like phenotype (dADSC), which showed attachment and proliferation on the films, maintenance of glial cell markers expression and enhancement of neurite outgrowth in co-culture with dorsal root ganglia (DRG) neurons.

    Transplantation of cells for nerve injuries remains sub-optimal due to their limited survival rates. In the second study, a chemical ischemia model (metabolically induced by sodium azide and 2-deoxyglucose) was established to investigate the differential effects of ischemia and serum deprivation on mesenchymal stem cells (MSCs). MSCs were more suseptible to combined than individual blockade of glycolysis and oxidative phosphorylation. Apoptotic and autophagy pathways were activated in the MSCs. Chemical ischemia or serum withdrawal alone induced a similar amount of cell death with significantly different intracellular ATP maintenance; but their effects were additive. The levels of various neurotrophin extracellular matrix and angiogenic factors expressed by the cells were shown to be differentially affected by ischemia but unaffected by changes in serum level. Stem cells isolated from both adipose tissue (ADSC) and bone marrow (BMSC) reacted similarly under these conditions. This chemical ischemia model will enable future screening of pharmacological agents to enhance the survival of MSCs under stress conditions.

    The mechanism underlying the neurotrophic potential of MSCs is unknown. In the third study in this thesis it is hypothesised that MSCs, upon stimulation with different growth factors, could produce brain derived neurotrophic factor (BNDF) with a similar molecular mechanism to that described in the nervous system. Within 24 hours of stimulation, ADSC and BMSC showed high secretion levels of BDNF, and these cells were able to enhance axonal outgrowth in DRG neurons at levels similar to long-term differentiated MSCs. Both the neuronal activity dependent promoterBDNFexon IV, along with full length protein encodingBDNFexon IX, were up-regulated upon stimulation.BDNFgating transcription factor, cyclic cAMP responsive element binding (CREB) protein, was also found to be activated but blocking of CREB phosphorylation with the small molecule inhibitor H89 did not suppress expression of BDNF protein suggesting compensatory pathways are involved.

    In summary, these studies indicate that MSCs are compatible with polyester based microporous scaffolds but the cells are highly susceptible to the stress conditions mimicking the hostile milieu at a nerve injury site. Preliminary studies hint at the molecular mechanism regulation BDNF expression in MSC and imply the interactions between MSCs and axons may play a role in the neurotrophic activity of the stem cells.

  • 365.
    Tse, Kai-Hei
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    The reactions of adipose tissue and bone marrow-derived stem cells in an ischaemia-like microenvironment2012In: Journal of tissue engineering and regenerative medicine, ISSN 1932-7005, Vol. 6, no 6, p. 473-485Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stem cells (MSCs) from adipose tissue and bone marrow are promising cell sources for autologous cell therapy of nerve injuries, as demonstrated by their intrinsic neurotrophic potential. However, extensive death of transplanted cells limits their full benefits. This study investigated the effects of ischaemia (metabolically induced by sodium azide and 2-deoxyglucose) and serum-derived mitogens on the viability and functional profile of MSCs in vitro. MSCs were more susceptible to combined, rather than individual, blockade of glycolysis and oxidative phosphorylation. Apoptosis and autophagy were involved in ischaemia-induced cell death. Chemical ischaemia alone and serum withdrawal alone induced a similar amount of cell death, with significantly different intracellular ATP maintenance. Combined ischaemia and serum deprivation had additive effects on cell death. Expression of the extracellular matrix (ECM) molecules laminin and fibronectin was attenuated under ischaemia and independent of serum level; however, BDNF and NGF levels remained relatively constant. Strong upregulation of VEGF and to a lesser extent angiopoietin-1 was observed under ischaemia but not in serum withdrawal conditions. Importantly, this study demonstrated similar reactions of MSCs derived from adipose and bone marrow tissue, in ischaemia-like and mitogen-deprived microenvironments in terms of viability, cellular energetics, cell death mechanisms and expression levels of various growth-promoting molecules. Also, the results suggest that ischaemia has a larger impact on the ability of MSCs to survive transplantation than withdrawal of mitogens. Copyright © 2011 John Wiley & Sons, Ltd.

  • 366.
    Tse, Kai-Hei
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Intrinsic mechanisms underlying the de novo BDNF expression of mesenchymal stem cellsManuscript (preprint) (Other academic)
  • 367.
    Tse, Kai-Hei
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Intrinsic mechanisms underlying the neurotrophic activity of adipose derived stem cells2015In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 331, no 1, p. 142-151Article in journal (Refereed)
    Abstract [en]

    Adipose derived stem cells (ADSC) can be differentiated into Schwann cell-like cells which enhance nerve function and regeneration. However, the signalling mechanisms underlying the neurotrophic potential of ADSC remain largely unknown. In this study, we hypothesised that ADSC, upon stimulation with a combination of growth factors, could rapidly produce brain derived neurotrophic factor (BDNF) with a similar molecular mechanism to that functioning in the nervous system. Within 48h of stimulation, ADSC demonstrated potent neurotrophic effects on dorsal root ganglion neurons, at a magnitude equivalent to that of the longer term differentiated Schwann cell-like cells. Stimulated ADSC showed rapid up-regulation of the neuronal activity dependent promoter BDNF exon IV along with an augmented expression of full length protein encoding BDNF exon IX. BDNF protein was secreted at a concentration similar to that produced by differentiated Schwann cell-like cells. Stimulation also activated the BDNF expression gating transcription factor, cAMP responsive element binding (CREB) protein. However, blocking phosphorylation of CREB with the protein kinase A small molecule inhibitor H89 did not suppress secretion of BDNF protein. These results suggest rapid BDNF production in ADSC is mediated through multiple compensatory pathways independent of, or in addition to, the CREB neuronal activation cascade.

  • 368.
    Tse, Kai-Hei
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Sun, Mingzhu
    University of Manchester.
    Mantovani, Cristina
    University of Manchester.
    Terenghi, Giorgio
    University of Manchester.
    Downes, Sandra
    University of Manchester.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    In vitro evaluation of polyester-based scaffolds seeded with adipose derived stem cells for peripheral nerve regeneration2010In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 95, no 3, p. 701-708Article in journal (Refereed)
    Abstract [en]

    To overcome the disadvantages of autografts for peripheral nerve repair, different methods such as artificial nerve conduits have been investigated for an alternative approach. This study demonstrated that solvent casting is a simple but efficient method to create thin polyester-based scaffolds for stem cell delivery. Using poly (ε-caprolactone) and poly (D,L-lactic acid), we produced scaffold films containing heterogenous depressions (pits) on the air surface with a size ranging from 0.5 to 30 μm(2). These scaffolds were moderately hydrophobic; however, they supported the differentiation of adipose derived stem cells (ADSC) into a Schwann cell-like phenotype. The differentiated ADSC (dADSC) expressed S100 protein and glial fibrillary acidic protein and readily adhered to the films and proliferated at a similar rate to those cultured on tissue culture polystyrene. Cells were also positive for proliferating cell nuclear antigen. Furthermore, dADSC retained functional activity and significantly enhanced neurite outgrowth from dorsal root ganglia neurons. This study suggests polymer scaffolds combined with dADSCs could be a promising therapy for peripheral nerve injuries.

  • 369.
    Vahid, Harandi M.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Susanne, Lindquist
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Shrikant, Shantilal Kolan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Thomas, Brännström
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jing-Xia, Liu
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Analysis of Neurotrophic Factors in Limb and Extraocular Muscles of Mouse Model of Amyotrophic Lateral Sclerosis2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, article id e109833Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is currently an incurable fatal motor neuron syndrome characterized by progressive weakness, muscle wasting and death ensuing 3–5 years after diagnosis. Neurotrophic factors (NTFs) are known to be important in both nervous system development and maintenance. However, the attempt to translate the potential of NTFs into the therapeutic options remains limited despite substantial number of approaches, which have been tested clinically. Using quantitative RT-PCR (qRT-PCR) technique, the present study investigated mRNA expression of four different NTFs: brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4) and glial cell line-derived neurotrophic factor (GDNF) in limb muscles and extraocular muscles (EOMs) from SOD1G93A transgenic mice at early and terminal stages of ALS. General morphological examination revealed that muscle fibres were well preserved in both limb muscles and EOMs in early stage ALS mice. However, in terminal ALS mice, most muscle fibres were either atrophied or hypertrophied in limb muscles but unaffected in EOMs. qRT-PCR analysis showed that in early stage ALS mice, NT-4 was significantly down-regulated in limb muscles whereas NT-3 and GDNF were markedly up-regulated in EOMs. In terminal ALS mice, only GDNF was significantly up-regulated in limb muscles. We concluded that the early down-regulation of NT-4 in limb muscles is closely associated with muscle dystrophy and dysfunction at late stage, whereas the early up-regulations of GDNF and NT-3 in EOMs are closely associated with the relatively well-preserved muscle morphology at late stage. Collectively, the data suggested that comparing NTFs expression between limb muscles and EOMs from different stages of ALS animal models is a useful method in revealing the patho-physiology and progression of ALS, and eventually rescuing motor neuron in ALS patients.

  • 370.
    Vicente, André
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Byström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Domellöf, Fatima Pedrosa
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Altered Signaling Pathways in Aniridia-Related Keratopathy2018In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 59, no 13, p. 5531-5541Article in journal (Refereed)
    Abstract [en]

    PURPOSE. To study the Notch1, Wnt/beta-catenin, sonic hedgehog (SHH), and mammalian target of rapamycin (mTOR) cell signaling pathways in naive and surgically treated corneas of aniridia cases with advanced aniridia-related keratopathy (ARK).

    METHODS. Two naive corneal buttons from patients with advanced ARK submitted to penetrating keratoplasty for the first time, one corneal button from an ARK patient that had undergone a keratolimbal allograft (KLAL), two corneal buttons from ARK patients who had previously undergone centered or decentered transplantation, and two adult healthy control corneas were processed for immunohistochemistry in this descriptive study. Antibodies specific against elements of the Notch1 (Notch1; Dlk1; Numb), Wnt/beta-catenin (Wnt5a; Wnt7a; beta-catenin), SHH (glioma-associated oncogene homolog [Gli1]; Hes1), and mTOR (mTOR1; ribosomal protein S6 [rpS6]) signaling pathways were used as well as antibodies against PAX6 and keratin 13 (Krt13).

    RESULTS. All ARK corneas presented signs of conjunctivalization and analogous signaling pathway changes in the subepithelial pannus and epithelium, with decreased detection of the Notch1 signaling pathway and an increased presence of the Notch1 inhibitors Numb and Dlk1. Increased detections of Wnt/beta-catenin (enhanced presence of Wnt5a, Wnt7a, and beta-catenin), SHH (detection of Gli1 and Hes1), and mTOR (identification of mTOR and rpS6) signaling pathways were found in the subepithelial pannus and epithelium of all ARK corneas, when compared with normal controls.

    CONCLUSIONS. The similarity in pathway alterations found in all ARK corneas, irrespective of limbal stem cell transplantation, further supports the discussion on the role of host-specific factors and limbal stem cell deficiency in ARK.

  • 371.
    Vicente, André
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Byström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Domellöf, Fatima Pedrosa
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Aniridia-related Keratopathy Relevant Cell Signaling Pathways in Human Fetal CorneasManuscript (preprint) (Other academic)
  • 372. Virtanen, Ismo
    et al.
    Banerjee, M
    Palgi, J
    Korsgren, O
    Lukinius, A
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kikkawa, Y
    Sekiguchi, K
    Hukkanen, M
    Konttinen, Y T
    Otonkoski, T
    Blood vessels of human islets of Langerhans are surrounded by a double basement membrane.2008In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 51, no 7, p. 1181-91Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: Based on mouse study findings, pancreatic islet cells are supposed to lack basement membrane (BM) and interact directly with vascular endothelial BM. Until now, the BM composition of human islets has remained elusive. METHODS: Immunohistochemistry with specific monoclonal and polyclonal antibodies as well as electron microscopy were used to study BM organisation and composition in human adult islets. Isolated islet cells and function-blocking monoclonal antibodies and recombinant soluble Lutheran peptide were further used to study islet cell adhesion to laminin (Lm)-511. Short-term cultures of islets were used to study Lutheran and integrin distribution. RESULTS: Immunohistochemistry revealed a unique organisation for human Lm-511/521 as a peri-islet BM, which co-invaginated into islets with vessels, forming an outer endocrine BM of the intra-islet vascular channels, and was distinct from the vascular BM that additionally contained Lm-411/421. These findings were verified by electron microscopy. Lutheran glycoprotein, a receptor for the Lm alpha5 chain, was found prominently on endocrine cells, as identified by immunohistochemistry and RT-PCR, whereas alpha(3) and beta(1) integrins were more diffusely distributed. High Lutheran content was also found on endocrine cell membranes in short-term culture of human islets. The adhesion of dispersed beta cells to Lm-511 was inhibited equally effectively by antibodies to integrin and alpha(3) and beta(1) subunits, and by soluble Lutheran peptide. CONCLUSIONS/INTERPRETATION: The present results disclose a hitherto unrecognised BM organisation and adhesion mechanisms in human pancreatic islets as distinct from mouse islets.

  • 373.
    Virtanen, Ismo
    et al.
    University of Helsinki.
    Korhonen, Matti
    Petäjäniemi, Noora
    Karhunen, Tuula
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Sorokin, Lydia M
    Konttinen, Yrjö T
    Laminin isoforms in fetal and adult human adrenal cortex2003In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 88, no 10, p. 4960-4966Article in journal (Refereed)
    Abstract [en]

    Laminin has been proposed to influence the function of human adrenal cortex. We have studied the distribution of laminin (Ln) chains using immunofluorescence in human fetal and adult adrenal cortex. In the fetal gland Ln alpha2- and alpha5-chains were weakly expressed in the definitive zone, whereas Ln alpha4-, beta1-, and gamma1-chains occurred around vessels. In the adult gland, Ln alpha2-, alpha5-, and gamma1-chains were found in epithelial basement membranes (BM) in all cortical zones, Ln alpha4-chain in vessels, Ln beta1-chain in outer zone, and Ln beta2-chain in the two inner zones of the cortex, respectively. Among the integrins in adult gland, integrin alpha(3)-subunit was confined to basal surfaces of cortical cells, alpha(6) to vessels, alpha(1) to the stroma, and alpha(2) diffusely to epithelial cells. Lutheran glycoprotein and dystroglycan occurred in the fetal gland diffusely in the definitive zone and throughout the epithelium in the adult. The isoform composition of BM of the adult adrenal gland is distinct, with Ln-2 and -10 in BM of the outer zone and Ln-4 and -11 in BM of the two inner zones. The results suggest that integrin alpha(3)beta(1) and Lutheran are candidate receptors for Ln-10 and -11, whereas dystroglycan probably binds Ln-2 and -4.

  • 374. Wang, Zhaohui
    et al.
    Glenn, Honor
    Brown, Christine
    Valavanis, Christos
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Seth, Anandita
    Thomas, Jeanne E
    Karlstrom, Rolf O
    Schwartz, Lawrence M
    Regulation of muscle differentiation and survival by Acheron.2009In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 126, no 8-9, p. 700-9Article in journal (Refereed)
    Abstract [en]

    Acheron (Achn), a phylogenetically-conserved member of the Lupus antigen family of RNA binding proteins, was initially identified as a novel cell death-associated gene from the intersegmental muscles of the tobacco hawkmoth Manduca sexta. C(2)C(12) cells are a standard model for the study of myogenesis. When deprived of growth factors, these cells can be induced to: form multinucleated myotubes, arrest as quiescent satellite-like reserve cells, or undergo apoptosis. Achn expression is induced in myoblasts that form myotubes and acts upstream of the muscle specific transcription factor MyoD. Forced expression of ectopic Achn resulted in the formation of larger myotubes and massive reserve cell death relative to controls. Conversely, dominant-negative or antisense Achn blocked myotube formation following loss of growth factors, suggesting that Achn plays an essential, permissive role in myogenesis. Studies in zebrafish embryos support this hypothesis. Reduction of Achn with antisense morpholinos led to muscle fiber loss and an increase in the number of surviving cells in the somites, while ectopic Achn enhanced muscle fiber formation and reduced cell numbers. These results display a crucial evolutionarily conserved role for Achn in myogenesis and suggest that it plays key roles in the processes of differentiation and self-renewal.

  • 375. Ward, Ella Rose
    et al.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Gaida, Jamie E.
    Fat pads adjacent to tendinopathy: more than a coincidence?2016In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 50, no 24, p. 1491-1492Article in journal (Refereed)
  • 376.
    Welin, Dag
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery.
    Neuroprotection and axonal regeneration after peripheral nerve injury2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Following microsurgical reconstruction of injured peripheral nerves, severed axons are able to undergo spontaneous regeneration. However, the functional result is always unsatisfactory with poor sensory recovery and reduced motor function. One contributing factor is the retrograde neuronal death, which occurs in the dorsal root ganglia (DRG) and in the spinal cord. An additional clinical problem is the loss of nerve tissue that often occurs in the trauma zone and which requires “bridges” to reconnect separated nerve ends. The present thesis investigates the extent of retrograde degeneration in spinal motoneurons and cutaneous and muscular afferent DRG neurons after permanent axotomy and following treatment with N-acetyl-cysteine (NAC). In addition, it examines the survival and growth-promoting effects of nerve reconstructions performed by primary repair and peripheral nerve grafting in combination with NAC treatment.

    In adult rats, cutaneous sural and muscular medial gastrocnemius DRG neurons and spinal motoneurons were retrogradely labeled with fluorescent tracers from the homonymous transected nerves. Survival of labeled neurons was assessed at different time points after nerve transection, ventral root avulsion and ventral rhizotomy. Axonal regeneration was evaluated using fluorescent tracers after sciatic axotomy and immediate nerve repair. Intraperitoneal or intrathecal treatment with NAC was initiated immediately after nerve injury or was delayed for 1-2 weeks.

    Counts of labeled gastrocnemius DRG neurons did not reveal any significant retrograde cell death after nerve transection. Sural axotomy induced a delayed loss of DRG cells, which amounted to 43- 48% at 8-24 weeks postoperatively. Proximal transection of the sciatic nerve at 1 week after initial axonal injury did not further increase retrograde DRG degeneration, nor did it affect survival of corresponding motoneurons. In contrast, rhizotomy and ventral root avulsion induced marked 26- 53% cell loss among spinal motoneurons. Primary repair or peripheral nerve grafting supported regeneration of 53-60% of the motoneurons and 47-49% of the muscular gastrocnemius DRG neurons at 13 weeks postoperatively. For the cutaneous sural DRG neurons, primary repair or peripheral nerve grafting increased survival by 19-30% and promoted regeneration of 46-66% of the cells. Regenerating sural and medial gastrocnemius DRG neurons upregulate transcription of peripherin and activating transcription factor 3. The gene expression of the structural neurofilament proteins of high molecular weight was significantly downregulated following injury in both regenerating and non-regenerating sensory neurons. Treatment with NAC was neuroprotective for spinal motoneurons after ventral rhizotomy and avulsion, and sural DRG neurons after sciatic nerve injury. However, combined treatment with nerve graft and NAC had significant additive effect on neuronal survival and also increased the number of sensory neurons regenerating across the graft. In contrast, NAC treatment neither affected the number of regenerating motoneurons nor the number of myelinated axons in the nerve graft and in the distal nerve stump.

    In summary, the present results demonstrate that cutaneous sural sensory neurons are more sensitive to peripheral nerve injury than muscular gastrocnemius DRG cells. Moreover, the retrograde loss of cutaneous DRG cells taking place despite immediate nerve repair would still limit recovery of cutaneous sensory functions. Experimental data also show that NAC provides a highly significant degree of neuroprotection in animal models of adult nerve injury and could be combined with nerve grafting to further attenuate retrograde neuronal death and to promote functional regeneration.

  • 377.
    Welin, Dag
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kellerth, Jan-Olof
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Effects of N-acetyl-cysteine on the survival and regeneration of sural sensory neurons in adult rats2009In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1287, no 1, p. 58-66Article in journal (Refereed)
    Abstract [en]

    Microsurgical reconstruction of injured peripheral nerves often results in limited functional recovery. One contributing factor is the retrograde neuronal degeneration of sensory neurons in the dorsal root ganglia (DRG) and of motor neurons in the spinal cord. The present study investigates the neuroprotective and growth-promoting effects of N-acetyl-cysteine (NAC) on sensory DRG neurons and spinal motoneurons after sciatic axotomy and nerve grafting in adult rats. Sciatic axotomy and nerve grafting were performed at 1 week after sural DRG neurons and motoneurons were retrogradely labeled with the fluorescent tracer Fast Blue. To assess the efficacy of axonal regeneration, a second fluorescent dye Fluoro-Ruby was applied distal to the graft at 12 weeks after nerve repair. At 8-13 weeks after axotomy, only 52-56% of the sural sensory neurons remained in the lumbar DRG, while the majority of motoneurons survived the sciatic nerve injury. Nerve grafting alone or continuous intrathecal NAC treatment (2.4 mg/day) improved survival of sural DRG neurons. Combined treatment with nerve graft and NAC had significant additive effect on neuronal survival and also increased the number of sensory neurons regenerating across the graft. However, NAC treatment neither affected the number of regenerating motoneurons nor the number of myelinated axons in the nerve graft or in the distal nerve stump. The present results demonstrate that NAC provides a highly significant effect of neuroprotection in an animal nerve injury model and that combination with nerve grafting further attenuates retrograde cell death and promotes regeneration of sensory neurons.

  • 378.
    West, Christian A
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery.
    Davies, Karen A
    Hart, Andrew M
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery.
    Williams, Steve R
    Terenghi, Giorgio
    Volumetric magnetic resonance imaging of dorsal root ganglia for the objective quantitative assessment of neuron death after peripheral nerve injury.2007In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 203, no 1, p. 22-33Article in journal (Refereed)
    Abstract [en]

    Prevention of neuron death after peripheral nerve injury is vital to regaining adequate cutaneous innervation density and quality of sensation, and while experimentally proven neuroprotective therapies exist, there lacks suitable clinical outcome measures for translational research. Axotomized dorsal root ganglia (DRG) histologically exhibit volume reduction in proportion to the amount of neuronal death within them. Hence, this study evaluated the validity of using magnetic resonance imaging (MRI) to quantify DRG volume as a proxy measure of cell death. A high-resolution 3D MRI sequence was developed for volumetric quantification of the L4 DRG in the rat sciatic nerve model. An unoperated "control" group (n=4), and a "nerve transection" group (n=6), 4 weeks after axotomy, were scanned. Accuracy and validity of the technique were evaluated by comparison with morphological quantification of DRG volume and stereological counts of surviving neurons (optical fractionator). The technique was precise (coefficient of variation=4.3%), highly repeatable (9% variability), and sensitive (mean 15.0% volume reduction in axotomized ganglia detected with statistical significance: p<0.01). MRI showed strong and highly significant correlation with morphological measures of DRG volume loss (r=0.90, p<0.001), which in turn correlated well with neuron loss (r=0.75, p<0.05). MRI similarly exhibited direct correlation with neuron loss (r=0.67, p<0.05) with consistent agreement. MRI volumetric quantification of DRG is therefore a valid in vivo measure of neuron loss. As a non-invasive, objective measure of neuronal death after nerve trauma this technique has potential as a diagnostic modality and a quantitative tool for clinical studies of neuroprotective agents.

  • 379.
    West, Christian A
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Blond McIndoe Research Laboratories, University of Manchester, Manchester, UK.
    Hart, Adrew M
    Terenghi, Giorgio
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Analysis of the dose-response of N-acetylcysteine in the prevention of sensory neuronal loss after peripheral nerve injury2007In: How to Improve the Results of Peripheral Nerve Surgery / [ed] H. Millesi, R. Schmidhammer, Springer, 2007, Vol. 100, p. 29-31Chapter in book (Other academic)
    Abstract [en]

    BACKGROUND: N-Acetylcysteine (NAC) is a safe pharmaceutical agent known to protect cells from oxidative damage. Following peripheral nerve transection, NAC has been found to eliminate sensory neuronal loss. This study examines the dose-response relationship of NAC in preventing neuronal death. METHODS AND FINDINGS: The rat sciatic nerve transection model was used, and stereological quantification of sensory neuron survival carried out at two weeks post-axotomy. NAC was administered systemically as an intraperitoneal injection to five groups of rats at a range of doses (1-300 mg/kg/day). Significant neuronal loss was observed in the 1 mg/kg/day dosage group (18.5% loss, p = 0.067 vs. sham treatment). A degree of neuroprotection occurred with 10 mg/kg/day (9.1% loss, p &lt; 0.005 vs. control), whilst there was no significant loss with either 150 or 300 mg/kg/day. CONCLUSIONS: The prevention of sensory neuronal loss with NAC is dose dependent and effective over a wide therapeutic range. This analysis confirms the efficacy of systemic administration and provides a dose framework with which NAC has clinical potential to improve outcome after peripheral nerve trauma.

  • 380.
    West, Christian Alexander
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Ljungberg, Christina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Hart, Andrew
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Plastic Surgery Research, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom, Canniesburn Plastic Surgery Unit, Scottish National Brachial Plexus Service, Glasgow Royal Infirmary, Glasgow, United Kingdom.
    Sensory neuron death after upper limb nerve injury and protective effect of repair: clinical evaluation using volumetric magnetic resonance imaging of dorsal root Ganglia.2013In: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 73, no 4, p. 632-640Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Extensive death of sensory neurons after nerve trauma depletes the number of regenerating neurons, contributing to inadequate cutaneous innervation density and poor sensory recovery. Experimentally proven neuroprotective neoadjuvant drugs require noninvasive in vivo measures of neuron death to permit clinical trials. In animal models of nerve transection, magnetic resonance imaging (MRI) proved a valid tool for quantifying sensory neuron loss within dorsal root ganglia (DRG) by measuring consequent proportional shrinkage of respective ganglia.

    OBJECTIVE: This system is investigated for clinical application after upper limb nerve injury and microsurgical nerve repair.

    METHODS: A 3-T clinical magnet was used to image and measure volume (Cavalieri principle) of C7-T1 DRG in uninjured volunteers (controls, n = 14), hand amputees (unrepaired nerve injury, n = 5), and early nerve repair patients (median and ulnar nerves transected, microsurgical nerve repair within 24 hours, n = 4).

    RESULTS: MRI was well tolerated. Volumetric analysis was feasible in 74% of patients. A mean 14% volume reduction was found in amputees' C7 and C8 DRG (P < .001 vs controls). Volume loss was lower in median and ulnar nerve repair patients (mean 3% volume loss, P < .01 vs amputees), and varied among patients. T1 DRG volume remained unaffected.

    CONCLUSION: MRI provides noninvasive in vivo assessment of DRG volume as a proxy clinical measure of sensory neuron death. The significant decrease found after unrepaired nerve injury provides indirect clinical evidence of axotomy-induced neuronal death. This loss was less after nerve repair, indicating a neuroprotective benefit of early repair. Volumetric MRI has potential diagnostic applications and is a quantitative tool for clinical trials of neuroprotective therapies.

  • 381.
    West, Christian Alexander
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    McKay Hart, Andrew
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Terenghi, Giorgio
    Manchester University.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Sensory Neurons of the Human Brachial Plexus: A Quantitative Study Employing Optical Fractionation and In-Vivo Volumetric Magnetic Resonance Imaging.2012In: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 70, no 5, p. 1183-1194Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Extensive neuron death following peripheral nerve trauma is implicated in poor sensory recovery. Translational research for experimentally proven neuroprotective drugs requires knowledge of the numbers and distribution of sensory neurons in the human upper limb, and a novel non-invasive clinical measure of neuron loss. OBJECTIVE: To compare optical fractionation and volumetric MRI of dorsal root ganglia (DRG) in histological quantification and objective clinical assessment of human brachial plexus sensory neurons. METHODS: Bilateral C5-T1 DRG were harvested from 5 human cadavers for stereological volume measurement and sensory neuron counts (optical fractionator). MRI scans were obtained from 14 normal volunteers for volumetric analysis of C5-T1 DRG. RESULTS: 425,409 (SD 15,596) sensory neurons innervate the brachial plexus with a significant difference in neuron counts and DRG volume between segmental levels (p<0.0001), with C7 ganglion containing the most. DRG volume correlated with neuron counts (r=0.75, p<.001). Vertebral artery pulsation hindered C5&6 imaging, yet high resolution MRI of C7, C8 and T1 DRG permitted unbiased volume measurement. In accord with histological analysis, MRI confirmed a significant difference between C7, C8 and T1 DRG volume (p<.001), inter-individual variability (COV 15.3%), and sex differences (p=.04). Slight right-left (R/L) sided disparity in neuron counts (2.5%, p=.04) was possibly related to hand dominance, but no significant volume disparity existed. CONCLUSION: Neuron counts for the human brachial plexus are presented. These correlate with histological DRG volumes and concur with volumetric MRI results in human volunteers. Volumetric MRI of C7-T1 DRG is a legitimate non-invasive proxy measure of sensory neurons for clinical study.

  • 382.
    Westermark, T
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Isaksson, T
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Holmberg, P
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kjörell, U
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Increase in bombesin-like peptides in the spinal cord after dexamethasone treatment of adrenalectomized rats1999In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 275, no 3, p. 179-182Article in journal (Refereed)
    Abstract [en]

    The potential influence of corticosteroids on the bombesin (BN)-like peptide family is unknown. Therefore, the effects of adrenalectomy (ADX) on the nervous system of Sprague-Dawley rats, some of them being treated with high doses of the synthetic glucocorticoid dexamethasone (DEX), were investigated. After 8-10 days of treatment, the rats were sacrificed and tissues were prepared for radioimmunoassay (RIA) and immunohistochemical examination. We found an increase in BN-like immunoreactivity in the superficial layers of the dorsal horn of the lumbar spinal cord in the ADX + DEX animals. This increase was confirmed by RIA (P < 0.05). The observations show that the expression of BN-like peptides is influenced by glucocorticoids. The altered levels of BN-like peptides may be related to the trophic and antinociceptive effects previously reported for these peptides. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

  • 383.
    Westermark, T
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Kjörell, U
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Increased content of bombesin/GRP in human synovial fluid in early arthritis: different pattern compared with substance P2001In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 19, no 6, p. 715-720Article in journal (Refereed)
    Abstract [en]

    Objective Bombesin (BN) and the mammalian homologue gastrin-releasing peptide (GRP) are known trophic factors, neurotransmitters and paracrine hormones. BN/GRP has not previously been demonstrated in synovial fluid. In this study, the amounts of BN/GRP and substance P (SP) present in synovial fluid from the knee joints of patients with rheumatoid arthritis (RA) and of healthy, controls were measured.

    Methods Synovial fluid from the knee joint was collected from patients with either longstanding RA (n = 32) or early arthritis (symptoms for < 12 months; n = 9) and from control subjects, i.e., individuals without known joint disease (n = 10). These samples were analyzed using radioimmunoassays.

    Results Levels of BN/GRP-like peptide were below the assay detection limits in synovial fluid from controls. Detectable levels of immunoreactive BN/GRP were present in the majority of patients with either longstanding RA or early arthritis. The levels were significantly higher in the synovial fluid from patients classified as having early, arthritis compared with those with longstanding RA (p < 0.05). There was a strong correlation between BN/GRP levels and the number of leukocytes in the synovial fluid in the patients with early arthritis. The levels of SP-like peptide in the patients, whether with early arthritis or longstanding RA, were significantly elevated compared with controls. However there was no difference in the levels between these two patient groups.

    Conclusions These observations show that BN/GRP-like peptide is present in the synovial fluid of joints affected by arthritis and that the pattern of BN/GRP increase differs from that of SP It appears as if the presence of BN/GRP is particularly related to the early processes of joint involvement. These observations are of interest because BN/GRP has well-known trophic and paracrine effects and chondrocytes have recently been shown to produce neuropeptides such as BN/GRP.

  • 384.
    Wiberg, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Clas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Wahlström, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Dahlin, Lars B
    Plexus brachialis-skador hos vuxna: Tidig nervreparation ger bättre kliniskt slutresultat2009In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, no 9, p. 586-590Article in journal (Refereed)
    Abstract [sv]

    Unga personer kan drabbas av skador på plexus brachialis – armens nervfläta – vid högenergitrauma.

    Medicinsk prioritering av patientens samtliga skador för adekvata åtgärder ska alltid göras vid stort trauma.

    Noggrann och tidig, eventuellt upprepad, klinisk neurologisk diagnostik kompletterad med tex MRI, DT-myelografi och neurofysiologiska undersökningar ska göras för att kartlägga plexusskadan.

    Neurobiologisk forskning visar att celldöd kan minskas och nervutväxt förbättras vid tidig nervreparation.

    Olika reparations- och rekonstruktionstekniker används beroende på plexusskadans omfattning och lokalisation.

    Tidig kirurgi och rekonstruktion vid plexusskador förbättrar det kliniska slutresultatet.

    Rehabiliteringen är omfattande och inkluderar ett adekvat omhändertagande av smärtproblematik.

  • 385.
    Wiberg, Rebecca
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    An exploration of the mechanisms behind peripheral nerve injury2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Despite surgical innovation, the sensory and motor outcome after peripheral nerve injury is incomplete. In this thesis, the biological pathways potentially responsible for the poor functional recoveries were investigated in both the distal nerve stump/target organ, spinal motoneurons and dorsal root ganglia (DRG). The effect of delayed nerve repair was determined in a rat sciatic nerve transection model. There was a dramatic decline in the number of regenerating motoneurons and myelinated axons found in the distal nerve stumps of animals undergoing nerve repair after a delay of 3 and 6 months. RT-PCR of the distal nerve stumps showed a decline in expression of Schwann cells (SC) markers, with a progressive increase in fibrotic and proteoglycan scar markers, with increased delayed repair time. Furthermore, the yield of SC which could be isolated from the distal nerve segments progressively fell with increased delay in repair time. Consistent with the impaired distal nerve stumps the target medial gastrocnemius (MG) muscles at 3- and 6-months delayed repair were atrophied with significant declines in wet weights (61% and 27% compared with contralateral sides). The role of myogenic transcription factors, muscle specific microRNAs and musclespecific E3 ubiquitin ligases in the muscle atrophy was investigated in both gastrocnemius and soleus muscles following either crush or nerve transection injury. In the crush injury model, the soleus muscle showed significantly increased recovery in wet weight at days 14 and 28 (compared with day 7) which was not the case for the gastrocnemius muscle which continued to atrophy. There was a significantly more pronounced up-regulation of MyoD expression in the denervated soleus muscle compared with the gastrocnemius muscle. Conversely, myogenin was more markedly elevated in the gastrocnemius versus soleus muscles. The muscles also showed significantly contrasting transcriptional regulation of the microRNAs miR-1 and miR-206. MuRF1 and Atrogin-1 showed the highest levels of expression in the denervated gastrocnemius muscle. Morphological and molecular changes in spinal motoneurons were compared after L4-L5 ventral root avulsion (VRA) and distal peripheral nerve axotomy (PNA). Neuronal degeneration was indicated by decreased immunostaining for microtubule-associated protein-2 in dendrites and synaptophysin in presynaptic boutons after both VRA and PNA. Immunostaining for ED1-reactive microglia and GFAPpositive astrocytes was significantly elevated in all experimental groups. qRT-PCR analysis and Western blotting of the ventral horn from L4-L5 spinal cord segments revealed a significant upregulation of apoptotic cell death mediators including caspases-3 and -8 and a range of related death receptors following VRA. In contrast, following PNA, only caspase-8 was moderately upregulated. The mechanisms of primary sensory neuron degeneration were also investigated in the DRG following peripheral nerve axotomy, where several apoptotic pathways including those involving the endoplasmic reticulum were shown to be upregulated. In summary, these results show that the critical time point after which the outcome of regeneration becomes too poor appears to be 3-months. Both proximal and distal injury affect spinal motoneurons morphologically, but VRA induces motoneuron degeneration mediated through both intrinsic and extrinsic apoptotic pathways. Primary sensory neuron degeneration involves several different apoptotic pathways, including the endoplasmic reticulum.

  • 386.
    Wiberg, Rebecca
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Jonsson, Samuel
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Investigation of the Expression of Myogenic Transcription Factors, microRNAs and Muscle-Specific E3 Ubiquitin Ligases in the Medial Gastrocnemius and Soleus Muscles following Peripheral Nerve Injury2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, article id e0142699Article in journal (Refereed)
    Abstract [en]

    Despite surgical innovation, the sensory and motor outcome after a peripheral nerve injury remains incomplete. One contributing factor to the poor outcome is prolonged denervation of the target organ, leading to apoptosis of both mature myofibres and satellite cells with subsequent replacement of the muscle tissue with fibrotic scar and adipose tissue. In this study, we investigated the expression of myogenic transcription factors, muscle specific microRNAs and muscle-specific E3 ubiquitin ligases at several time points following denervation in two different muscles, the gastrocnemius (containing predominantly fast type fibres) and soleus (slow type) muscles, since these molecules may influence the degree of atrophy following denervation. Both muscles exhibited significant atrophy (compared with the contra-lateral sides) at 7 days following either a nerve transection or crush injury. In the crush model, the soleus muscle showed significantly increased muscle weights at days 14 and 28 which was not the case for the gastrocnemius muscle which continued to atrophy. There was a significantly more pronounced up-regulation of MyoD expression in the denervated soleus muscle compared with the gastrocnemius muscle. Conversely, myogenin was more markedly elevated in the gastrocnemius versus soleus muscles. The muscles also showed significantly contrasting transcriptional regulation of the microRNAs miR-1 and miR-206. MuRF1 and Atrogin-1 showed the highest levels of expression in the denervated gastrocnemius muscle. This study provides further insights regarding the intracellular regulatory molecules that generate and maintain distinct patterns of gene expression in different fibre types following peripheral nerve injury.

  • 387.
    Wiberg, Rebecca
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    A Morphological and Molecular Characterization of the Spinal Cord after Ventral Root Avulsion or Distal Peripheral Nerve Axotomy Injuries in Adult Rats2017In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 34, no 3, p. 652-660Article in journal (Refereed)
    Abstract [en]

    Retrograde cell death in sensory dorsal root ganglion cells following peripheral nerve injury is well established. However, available data regarding the underlying mechanism behind injury induced motoneuron death are conflicting. By comparing morphological and molecular changes in spinal motoneurons after L4-L5 ventral root avulsion (VRA) and distal peripheral nerve axotomy (PNA) 7 and 14 days postoperatively, we aimed to gain more insight about the mechanism behind injury-induced motoneuron degeneration. Morphological changes in spinal cord were assessed by using quantitative immunohistochemistry. Neuronal degeneration was revealed by decreased immunostaining for microtubuleassociated protein-2 in dendrites and synaptophysin in presynaptic boutons after both VRA and PNA. Significant motoneuron atrophy was already observed at 7 days post-injury, independently of injury type. Immunostaining for ED1 reactive microglia was significantly elevated in all experimental groups, as well as the astroglial marker glial fibrillary acidic protein (GFAP). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of the ventral horn from L4-L5 spinal cord segments revealed a significant upregulation of genes involved in programmed cell death including caspase-3, caspase-8, and related death receptors TRAIL-R, tumor necrosis factor (TNF)-R, and Fas following VRA. In contrast, following PNA, caspase-3 and the death receptor gene expression levels did not differ from the control, and there was only a modest increased expression of caspase-8. Moreover, the altered gene expression correlated with protein changes. These results show that the spinal motoneurons reacted in a similar fashion with respect to morphological changes after both proximal and distal injury. However, the increased expression of caspase-3, caspase-8, and related death receptors after VRA suggest that injury- induced motoneuron degeneration is mediated through an apoptotic mechanism, which might involve both the intrinsic and the extrinsic pathways.

  • 388.
    Wiberg, Rebecca
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Evaluation of apoptotic pathways in dorsal root ganglion neurons following peripheral nerve injury2018In: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, p. 779-785Article in journal (Refereed)
    Abstract [en]

    Peripheral nerve injuries induce significant sensory neuronal cell death in the dorsal root ganglia (DRG); however, the role of specific apoptotic pathways is still unclear. In this study, we performed peripheral nerve transection on adult rats, after which the corresponding DRGs were harvested at 7, 14, and 28 days after injury for subsequent molecular analyses with quantitative reverse transcription-PCR, western blotting, and immunohistochemistry. Nerve injury led to increased levels of caspase-3 mRNA and active caspase-3 protein in the DRG. Increased expression of caspase-8, caspase-12, caspase-7, and calpain suggested that both the extrinsic and the endoplasmic reticulum (ER) stress-mediated apoptotic pathways were activated. Phosphorylation of protein kinase R-like ER kinase further implied the involvement of ER-stress in the DRG. Phosphorylated protein kinase R-like ER kinase was most commonly associated with isolectin B4 (IB4)-positive neurons in the DRG and this may provide an explanation for the increased susceptibility of these neurons to die following nerve injury, likely in part because of an activation of the ER-stress response.

  • 389.
    Wilson, Andrew D H
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Hart, Andrew
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Anatomi. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Terenghi, Giorgio
    Blond McIndoe Research Laboratory, Plastic and Reconstructive Surgery Research, University of Manchester, Manchester, UK.
    Delayed acetyl-L-carnitine administration and its effect on sensory neuronal rescue after peripheral nerve injury.2008In: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1532-1959, Vol. 60, no 2, p. 114-118Article in journal (Refereed)
    Abstract [en]

    Protection of sensory neurons after peripheral nerve injury is clinically crucial since inadequate sensory recovery is seriously affected by the death of up to 40% of sensory neurons. Immediate acetyl-L-carnitine (ALCAR) treatment eliminates this cell loss, but may not always be clinically feasible, hence we studied the effect of delaying the initiation of ALCAR treatment. Five groups of rats (n=5 per group) underwent unilateral sciatic nerve axotomy. ALCAR treatment (50 mg/kg/day) was initiated immediately, or after delays of 6 h, 24 h or 7 days after injury. A sham-treated group served as control. L4 and L5 dorsal root ganglia were harvested bilaterally 2 weeks after injury and stereological sensory neuron counts were obtained. Immediate sham treatment provided no neuroprotection (25% loss). Cell loss was eliminated when ALCAR was commenced within

  • 390.
    Wilson, Andrew D H
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. University Department of Surgery, Blond McIndoe Centre, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
    Hart, Andrew
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. University Department of Surgery, Blond McIndoe Centre, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Terenghi, Giorgio
    University Department of Surgery, Blond McIndoe Centre, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
    Primary sensory neuronal rescue with systemic acetyl-L-carnitine following peripheral axotomy. A dose-response analysis2003In: British Journal of Plastic Surgery, ISSN 0007-1226, E-ISSN 1465-3087, Vol. 56, no 8, p. 732-739Article in journal (Refereed)
    Abstract [en]

    The loss of a large proportion of primary sensory neurons after peripheral nerve axotomy is well documented. As a consequence of this loss, the innervation density attained on completion of regeneration will never be normal, regardless of how well the individual surviving neurons regenerate. Acetyl-L-carnitine (ALCAR), an endogenous peptide in man, has been demonstrated to protect sensory neurons, thereby avoiding loss after peripheral nerve injury. In this study we examined the dose-response effect of ALCAR on the primary sensory neurons in the rat dorsal root ganglia (DRG) 2 weeks after sciatic nerve axotomy. Six groups of adult rats (n=5) underwent unilateral sciatic nerve axotomy, without repair, followed by 2 weeks systemic treatment with one of five doses of ALCAR (range 0.5-50 mg/kg/day), or normal saline. L4 and L5 dorsal root ganglia were then harvested bilaterally and sensory neuronal cell counts obtained using the optical disector technique. ALCAR eliminated neuronal loss at higher doses (50 and 10 mg/kg/day), while lower doses did result in loss (12% at 5 mg/kg/day, p<0.05; 19% at 1 mg/kg/day, p<0.001; 23% at 0.5 mg/kg/day, p<0.001) compared to contralateral control ganglia. Treatment with normal saline resulted in a 25% (p<0.001) loss, demonstrating no protective effect in accordance with previous studies.ALCAR preserves the sensory neuronal cell population after axotomy in a dose-responsive manner and as such, has potential for improving the clinical outcome following peripheral nerve trauma when doses in excess of 10 mg/kg/day are employed.

  • 391.
    Wilson, Andrew D H
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Hart, Andrew
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Terenghi, Giorgio
    Blond McIndoe Research Laboratories, Tissue Injury and Repair Group, University of Manchester, Room 3.106 Stopford Building, Oxford Road, Manchester M13 9PT, UK.
    Acetyl-l-carnitine increases nerve regeneration and target organ reinnervation: A morphological study2010In: Journal of Plastic, Reconstructive & Aesthetic Surgery, ISSN 1748-6815, E-ISSN 1532-1959, Journal of plastic, reconstructive & aesthetic surgery : JPRAS, ISSN 1878-0539, Vol. 63, no 7, p. 1186-1195Article in journal (Refereed)
    Abstract [en]

    Peripheral nerve injury frequently results in functional morbidity since standard management fails to adequately address many of the neurobiological hurdles to optimal regeneration. Neuronal survival and regeneration are neurotrophin dependent and require increased aerobic capacity. Acetyl-l-carnitine (ALCAR) facilitates this need and prevents neuronal loss. ALCAR is clinically safe and is shown here to significantly improve nerve regeneration and target organ reinnervation. Two groups of five rats underwent sciatic nerve division followed by immediate repair. One group received parenteral ALCAR (50mg/kg/day) from time of operation until termination at 12 weeks. A 'sham treatment' group received normal saline. A third group was left unoperated and did not receive any treatment. A segment of nerve was harvested between 5mm proximal and 10mm distal to the repair in operated groups, and at the corresponding level in the unoperated group. Mean axonal count in normal, non-axotomised nerve was 14,720 (SD 2378). That of the saline group (17,217 SD 1808) was not significantly different from normal nerve (P=0.0985). Mean number of myelinated axons in the ALCAR group (24,460 SD 3750) was significantly greater than both sham group (P<0.01) and normal nerve (P=0.0012). Mean myelin thickness in the saline treated group (0.408mum SD 0.067mum) was less than normal nerve (0.770mum SD 0.143mum) (P<0.001). Mean myelin thickness in the ALCAR group (0.627mum SD 0.052mum) was greater than the sham (saline) group (P<0.01) and not statistically different from normal nerve (P=0.07). ALCAR increased dermal PGP9.5 staining by 210% compared to sham treatment (P<0.0001) and significantly reduced the mean percentage weight loss in gastrocnemius muscle (ALCAR group 0.203% vs. 0.312% in sham group P=0.015). ALCAR not only increases the number of regenerating nerve fibres but also morphologically improves the quality of regeneration and target organ reinnervation. Adjuvant ALCAR treatment may improve both sensory and motor outcomes and merits further investigation.

  • 392.
    Wählby, Lennart
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Achilles tendon injury: aspects on muscle structure and strength1978Doctoral thesis, comprehensive summary (Other academic)
  • 393.
    Yang, Lingling
    et al.
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Di, Guohu
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Qi, Xia
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Qu, Mingli
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Wang, Yao
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Duan, Haoyun
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Xie, Lixin
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Zhou, Qingjun
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor.2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 12, p. 4262-4274Article in journal (Refereed)
    Abstract [en]

    Substance P (SP) is a neuropeptide, predominantly released from sensory nerve fibers, with a potentially protective role in diabetic corneal epithelial wound healing. However, the molecular mechanism remains unclear. We investigated the protective mechanism of SP against hyperglycemia-induced corneal epithelial wound healing defects, using type 1 diabetic mice and high glucose-treated corneal epithelial cells. Hyperglycemia induced delayed corneal epithelial wound healing, accompanied with attenuated corneal sensation, mitochondrial dysfunction, and impairments of Akt-, EGFR-, and Sirt1-activation, as well as decreased reactive oxygen species (ROS) scavenging capacity. However, SP application promoted the epithelial wound healing, the recovery of corneal sensation, the improvement of mitochondrial function, and the reactivation of Akt, EGFR and Sirt1, as well as increased ROS scavenging capacity, in both diabetic mouse corneal epithelium and high glucose-treated corneal epithelial cells. The promotion of SP on diabetic corneal epithelial healing was completely abolished by a NK-1 receptor antagonist. Moreover, the subconjunctival injection of NK-1 receptor antagonist also caused diabetic corneal pathological changes in normal mice. In conclusion, the results suggest that SP-NK-1 receptor signaling plays a critical role in the maintenance of corneal epithelium homeostasis, and that SP signaling through the NK-1 recssssseptor contributes to the promotion of diabetic corneal epithelial wound healing by rescued activation of Akt, EGFR, and Sirt1, improvement of mitochondrial function, and increased ROS scavenging capacity.

  • 394. Yang, Lingling
    et al.
    Qu, Mingli
    Wang, Yao
    Duan, Haoyun
    Chen, Peng
    Wang, Ye
    Shi, Weiyun
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Zhou, Qingjun
    Trichostatin A Inhibits Transforming Growth Factor-beta-Induced Reactive Oxygen Species Accumulation and Myofibroblast Differentiation via Enhanced NF-E2-Related Factor 2-Antioxidant Response Element Signaling2013In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 83, no 3, p. 671-680Article in journal (Refereed)
    Abstract [en]

    Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-beta (TGF-beta)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-beta in the presence of TSA, the NAD(P) H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by alpha-smooth muscle actin (alpha-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H2O2, intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-beta-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, TSA also decreased cellular ROS and H2O2 accumulation induced by TGF-beta, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-beta-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling.

  • 395.
    Yu, F
    et al.
    Pennsylvania State University.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Larsson, L
    Human single masseter muscle fibers contain unique combinations of myosin and myosin binding protein C isoforms2002In: Journal of Muscle Research and Cell Motility, ISSN 0142-4319, E-ISSN 1573-2657, Vol. 23, no 4, p. 317-326Article in journal (Refereed)
    Abstract [en]

    Striated craniofacial and limb muscles differ in their embryological origin, regulatory program during myogenesis, and innervation. In an attempt to explore the effects of these differences on the striated muscle phenotype in humans, the expression of myosin and myosin-associated thick filament proteins were studied at the single fiber level both in the human jaw-closing masseter muscle and in two limb muscles (biceps brachii and quadriceps femoris muscles). In the masseter, unique combinations of myosin heavy chain (MyHC) and myosin binding protein C (MyBP-C) isoforms were observed at the single fiber level. Compared to the limb muscles, the MyHC isoform expression was more complex in the masseter while the opposite was observed for MyBP-C. In limb muscles, a coordinated expression of three MyHC and three MyBP-C isoforms were observed, i.e., single fibers contained one or two MyHC isoforms, and up to three MyBP-C isoforms. Also, the relative content of the different MyBP-C isoforms correlated with the MyHC isoform expression. In the masseter, on the other hand, up to five different MyHC isoforms could be observed in the same fiber, but only one MyBP-C isoform was identified irrespective MyHC isoform expression. This MyBP-C isoform had a migration rate similar to the slow MyBP-C isoform in limb muscle fibers. In conclusion, a unique myofibrillar protein isoform expression was observed in the human masseter muscle fibers, suggesting significant differences in structural and functional properties between muscle fibers from human masseter and limb muscles.

  • 396.
    Yu, J-G
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Thornell, Lars-Eric
    Eccentric contractions leading to DOMS do not cause loss of desmin nor fibre necrosis in human muscle.2002In: Histochemistry and Cell Biology, ISSN 0948-6143, Vol. 118, no 1, p. 29-34Article in journal (Refereed)
  • 397.
    Yu, J-G
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Evidence of transient increased permeability of sarcolemma upon eccentric exercise inducing delayed onset muscle soreness.Manuscript (Other academic)
  • 398.
    Yu, Ji-Guo
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bonnerud, Patrik
    Department of Health Sciences, Luleå University of Technology, Luleå.
    Eriksson, Anders
    Department of Health Sciences, Luleå University of Technology, Luleå.
    Stål, Per S.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Tegner, Yelverton
    Department of Health Sciences, Luleå University of Technology, Luleå.
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Effects of long term supplementation of anabolic androgen steroids on human skeletal muscle2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e105330Article in journal (Refereed)
    Abstract [en]

    The effects of long-term (over several years) anabolic androgen steroids (AAS) administration on human skeletal muscle are still unclear. In this study, seventeen strength training athletes were recruited and individually interviewed regarding self-administration of banned substances. Ten subjects admitted having taken AAS or AAS derivatives for the past 5 to 15 years (Doped) and the dosage and type of banned substances were recorded. The remaining seven subjects testified to having never used any banned substances (Clean). For all subjects, maximal muscle strength and body composition were tested, and biopsies from the vastus lateralis muscle were obtained. Using histochemistry and immunohistochemistry (IHC), muscle biopsies were evaluated for morphology including fiber type composition, fiber size, capillary variables and myonuclei. Compared with the Clean athletes, the Doped athletes had significantly higher lean leg mass, capillary per fibre and myonuclei per fiber. In contrast, the Doped athletes had significantly lower absolute value in maximal squat force and relative values in maximal squat force (relative to lean body mass, to lean leg mass and to muscle fiber area). Using multivariate statistics, an orthogonal projection of latent structure discriminant analysis (OPLS-DA) model was established, in which the maximal squat force relative to muscle mass and the maximal squat force relative to fiber area, together with capillary density and nuclei density were the most important variables for separating Doped from the Clean athletes (regression  =  0.93 and prediction  =  0.92, p<0.0001). In Doped athletes, AAS dose-dependent increases were observed in lean body mass, muscle fiber area, capillary density and myonuclei density. In conclusion, long term AAS supplementation led to increases in lean leg mass, muscle fiber size and a parallel improvement in muscle strength, and all were dose-dependent. Administration of AAS may induce sustained morphological changes in human skeletal muscle, leading to physical performance enhancement.

  • 399.
    Yu, Ji-Guo
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Carlsson, Lena
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Evidence for myofibril remodeling as opposed to myofibril damage in human muscles with DOMS: an ultrastructural and immunoelectron microscopic study.2004In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 121, no 3, p. 219-227Article in journal (Refereed)
    Abstract [en]

    The myofibrillar and cytoskeletal alterations observed in delayed onset muscle soreness (DOMS) caused by eccentric exercise are generally considered to represent damage. By contrast our recent immunohistochemical studies suggested that the alterations reflect myofibrillar remodeling (Yu and Thornell 2002; Yu et al. 2003). In the present study the same human muscle biopsies were further analyzed with transmission electron microscopy and immunoelectron microscopy. We show that the ultrastructural hallmarks of DOMS, Z-disc streaming, Z-disc smearing, and Z-disc disruption were present in the biopsies and were significantly more frequent in biopsies taken 2-3 days and 7-8 days after exercise than in those from controls and 1 h after exercise. Four main types of changes were observed: amorphous widened Z-discs, amorphous sarcomeres, double Z-discs, and supernumerary sarcomeres. We confirm by immunoelectron microscopy that the main Z-disc protein alpha-actinin is not present in Z-disc alterations or in the links of electron-dense material between Z-discs in longitudinal register. These alterations were related to an increase of F-actin and desmin, where F-actin was present within the strands of amorphous material. Desmin, on the other hand, was seen in less dense regions of the alterations. Our results strongly support that the myofibrillar and cytoskeletal alterations, considered to be the hallmarks of DOMS, reflect an adaptive remodeling of the myofibrils.

  • 400.
    Yu, Ji-Guo
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Fürst, Dieter O
    Department of Cell Biology, Institute for Biochemistry and Biology, University of Potsdam, Potsdam, Germany.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The mode of myofibril remodelling in human skeletal muscle affected by DOMS induced by eccentric contractions.2003In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 119, no 5, p. 383-93Article in journal (Refereed)
    Abstract [en]

    Myofibrillar Z-disc streaming and loss of the desmin cytoskeleton are considered the morphological hallmarks of eccentric contraction-induced injury. The latter is contradicted by recent studies where a focal increase of desmin was observed in biopsies taken from human muscles with DOMS. In order to determine the effects of eccentric contraction-induced alterations of the myofibrillar Z-disc, we examined the distribution of alpha-actinin, the Z-disc portion of titin and the nebulin NB2 region in relation to actin and desmin in DOMS biopsies. In biopsies taken 2-3 days and 7-8 days after exercise, we observed a significantly higher number of fibres showing focal areas lacking staining for alpha-actinin, titin and nebulin than in biopsies taken from control or 1 h after exercise. None of these proteins were part of Z-disc streamings but instead they were found in distinct patterns in areas characterised by altered staining for desmin and actin. These were preferentially seen in regions with increased numbers of sarcomeres in parallel myofibrils. We propose that these staining patterns represent different stages of sarcomere formation. These findings therefore support our previous suggestion that muscle fibres subjected to eccentric contractions adapt to unaccustomed activity by the addition of new sarcomeres.

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