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Harandi, V. M. (2016). A Muscle Perspective on the Pathophysiology of Amyotrophic Lateral Sclerosis: Differences between extraocular and limb muscles. (Doctoral dissertation). Umeå: Umeå universitet
Open this publication in new window or tab >>A Muscle Perspective on the Pathophysiology of Amyotrophic Lateral Sclerosis: Differences between extraocular and limb muscles
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder. ALS has been traditionally believed to be primarily a motor neuron disease. However, accumulating data indicate that loss of contact between the axons and the muscle fibres occurs early; long before the death of motor neurons and that muscle fibres may initiate motor neuron degeneration. Thus, the view of ALS is changing focus from motor neurons alone to also include the muscle fibres and the neuromuscular junctions (NMJs). While skeletal muscles are affected in ALS, oculomotor disturbances are not dominant features of this disease and extraocular muscles (EOMs) are far less affected than limb muscles. Why oculomotor neurons and EOMs are capable to be more resistant in the pathogenetic process of ALS is still unknown.

The overall goal of this thesis is to explore the pathophysiology of ALS from a muscle perspective and in particular study the expression and distribution of key neurotrophic factors (NTFs) and Wnt proteins in EOMs and limb muscles from ALS donors and from SOD1G93A transgenic mice. Comparisons were made with age-matched controls to distinguish between changes related to ALS and to ageing.

Results: Brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4) were present in EOMs and limb muscles at both mRNA and protein levels in control mice. The mRNA levels of BDNF, NT-3 and NT-4 were significantly lower in EOMs than in limb muscles of early and/or late control mice, indicating an intrinsic difference in NTFs expression between EOMs and limb muscles. qRT-PCR analysis showed significantly upregulated mRNA levels of NT-3 and GDNF in EOMs but significantly downregulated mRNA levels of NT-4 in limb muscles from SOD1G93A transgenic mice at early stage. The NTFs were detected immunohistochemically in NMJs, nerve axons and muscle fibres. The expression of BDNF, GDNF and NT-4 on NMJs of limb muscles, but not of EOMs, was significantly decreased in terminal stage ALS animals as compared to the limb muscles of the age-matched controls. In contrast, NTFs expression in intramuscular nerve axons did not present significant changes in either muscle group of early or late ALS mice. NTFs, especially BDNF and NT-4 were upregulated in some small-sized muscle fibres in limb muscles of late stage ALS mice. All the four Wnt isoforms, Wnt1, Wnt3a, Wnt5a and Wnt7a were detected in most axon profiles in all human EOMs with ALS, whereas significantly fewer axon profiles were positive in the human limb muscles except for Wnt5a. Similar differential patterns were found in myofibres, except for Wnt7a, where its expression was elevated within sarcolemma of limb muscle fibres. β-catenin, a marker of the canonical Wnt pathway was activated in a subset of myofibres in the EOMs and limb muscle in all ALS patients. In the SOD1G93A mouse, all four Wnt isoforms were significantly decreased in the NMJs at the terminal stage compared to age matched controls.

Conclusions: There were clear differences in NTF and Wnt expression patterns between EOM and limb muscle, suggesting that they may play a role in the distinct susceptibility of these two muscle groups to ALS. In particular, the early upregulation of GDNF and NT-3 in the EOMs might play a role in the preservation of the EOMs in ALS. Further studies are needed to determine whether these proteins and the pathways they control may be have a future potential as protecting agents for other muscles.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2016. p. 92
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1803
Keywords
Neuromuscular junctions, Extraocular muscles, Skeletal muscle, Neurotrophic factor, Wnt, Motor neuron disease, Amyotrophic lateral sclerosis, SOD1G93A mice
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-120219 (URN)978-91-7601-445-5 (ISBN)
Public defence
2016-06-08, KB3B1 (149), KBC-huset, KBC house, Umeå University, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2016-05-18 Created: 2016-05-11 Last updated: 2018-06-07Bibliographically approved
Harandi, V. M., Gaied, A. R., Brännström, T., Pedrosa-Domellöf, F. & Liu, J.-X. (2016). Unchanged neurotrophic factors and their receptors correlate with sparing in extraocular muscles in amyotrophic lateral sclerosis. Investigative Ophthalmology and Visual Science, 57(15), 6831-6842
Open this publication in new window or tab >>Unchanged neurotrophic factors and their receptors correlate with sparing in extraocular muscles in amyotrophic lateral sclerosis
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2016 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, no 15, p. 6831-6842Article in journal (Refereed) Published
Abstract [en]

Purpose: To investigate the impact of amyotrophic lateral sclerosis (ALS) on the extraocular muscles (EOMs) by examining the distribution of neurotrophic factors (NTFs) and their receptors in EOMs and limb muscles from ALS transgenic mice.

Methods: Muscle samples collected from transgenic mice overexpressing human superoxide dismutase type 1 mutations (SOD1G93A, the most widely used mouse model of ALS) at 50 and 150 days as well as age-matched controls were analyzed with immunohistochemistry using antibodies against brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4), glial cell line-derived neurotrophic factor (GDNF), and the neurotrophin receptors p75NTR, tyrosine kinase (Trk) receptor TrkB and TrkC, and GDNF family receptor alpha-1 (GFRα-1).

Results: There was an intrinsic difference in NTF expression between EOMs and limb muscles in control mice: EOMs presented significantly lower number of neuromuscular junctions (NMJs) labeled for BDNF and NT-4 at 50 days, and for BDNF and GDNF at 150 days, compared with the control limb muscles of corresponding age. In ALS transgenic mice at 150 days, NTF expression in limb muscles was significantly changed but not in EOMs: the limb muscles presented a significant decline in the number of NMJs labeled for BDNF, NT-4, GDNF, p75NTR, TrkB, and TrkC, which was not observed in EOMs.

Conclusions: The significant differences in expression of NTFs on NMJs between EOMs and limb muscles in both control and ALS transgenic mice suggest that NTF may be involved in the pathogenesis of ALS and the resistance of EOMs to the disease.

Place, publisher, year, edition, pages
Rockville: The association for research in vision and ophthalmology, 2016
Keywords
extraocular muscles, neuromuscular junctions, neurotrophin, amyotrophic lateral sclerosis, neurotrophic factor
National Category
Neurosciences
Research subject
Human Anatomy
Identifiers
urn:nbn:se:umu:diva-129395 (URN)10.1167/iovs.16-20074 (DOI)000392929500045 ()28002846 (PubMedID)2-s2.0-85007286240 (Scopus ID)
Available from: 2016-12-25 Created: 2016-12-25 Last updated: 2018-06-09Bibliographically approved
Spang, C., Harandi, V. M., Alfredsson, H. & Forsgren, S. (2015). Marked innervation but also signs of nerve degeneration in between the Achilles and plantaris tendons and presence of innervation within the plantaris tendon in midportion Achilles tendinopathy. Journal of Musculoskeletal and Neuronal Interactions - JMNI, 15(2), 197-206
Open this publication in new window or tab >>Marked innervation but also signs of nerve degeneration in between the Achilles and plantaris tendons and presence of innervation within the plantaris tendon in midportion Achilles tendinopathy
2015 (English)In: Journal of Musculoskeletal and Neuronal Interactions - JMNI, ISSN 1108-7161, Vol. 15, no 2, p. 197-206Article in journal (Refereed) Published
Abstract [en]

Objectives: The plantaris tendon is increasingly recognised as an important factor in midportion Achilles tendinopathy. Its innervation pattern is completely unknown. Methods: Plantaris tendons (n=56) and associated peritendinous tissue from 46 patients with midportion Achilles tendinopathy and where the plantaris tendon was closely related to the Achilles tendon were evaluated. Morphological evaluations and stainings for nerve markers [general (PGP9.5), sensory (CGRP), sympathetic (TH)], glutamate NMDA receptor and Schwann cells (S-100β) were made. Results: A marked innervation, as evidenced by evaluation for PGP9.5 reactions, occurred in the peritendinous tissue located between the plantaris and Achilles tendons. It contained sensory and to some extent sympathetic and NMDAR1-positive axons. There was also an innervation in the zones of connective tissue within the plantaris tendons. Interestingly, some of the nerve fascicles showed a partial lack of axonal reactions. Conclusion: New information on the innervation patterns for the plantaris tendon in situations with midportion Achilles tendinopathy has here been obtained. The peritendinous tissue was found to be markedly innervated and there was also innervation within the plantaris tendon. Furthermore, axonal degeneration is likely to occur. Both features should be further taken into account when considering the relationship between the nervous system and tendinopathy

Keywords
Plantaris Tendon, Achilles Tendinopathy, Pain, Innervation, Peritendinous Connective Tissue
National Category
Physiology
Identifiers
urn:nbn:se:umu:diva-103312 (URN)000356001800011 ()
Available from: 2015-05-20 Created: 2015-05-20 Last updated: 2018-06-07Bibliographically approved
Vahid, H. M., Susanne, L., Shrikant, S. K., Thomas, B. & Jing-Xia, L. (2014). Analysis of Neurotrophic Factors in Limb and Extraocular Muscles of Mouse Model of Amyotrophic Lateral Sclerosis. PLOS ONE, 9(10), Article ID e109833.
Open this publication in new window or tab >>Analysis of Neurotrophic Factors in Limb and Extraocular Muscles of Mouse Model of Amyotrophic Lateral Sclerosis
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2014 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 10, article id e109833Article in journal (Refereed) Published
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.

Keywords
neurotrophins, neurotrophic factor, limb muscles, extraocular muscles, ALS
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:umu:diva-96545 (URN)10.1371/journal.pone.0109833 (DOI)000346766200057 ()2-s2.0-84908116506 (Scopus ID)
Available from: 2014-11-21 Created: 2014-11-21 Last updated: 2023-03-24Bibliographically approved
McLoon, L. K., Harandi, V. M., Brännstrom, T., Andersen, P. M. & Liu, J.-X. (2014). Wnt and Extraocular Muscle Sparing in Amyotrophic Lateral Sclerosis. Investigative Ophthalmology and Visual Science, 55(9), 5482-5496
Open this publication in new window or tab >>Wnt and Extraocular Muscle Sparing in Amyotrophic Lateral Sclerosis
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2014 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 55, no 9, p. 5482-5496Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The extraocular muscles (EOM) and their motor neurons are spared in amyotrophic lateral sclerosis (ALS). In limb muscle axon retraction from the neuromuscular junctions occurs early in the disease. Wnts, a conserved family of secreted signaling molecules, play a critical role in neuromuscular junction formation. This is the first study to examine Wnt signaling for its potential involvement in maintenance of normal morphology in EOMs in ALS.

METHODS: EOM and limb muscle axons, neuromuscular junctions, and myofibers from control, aging, and ALS patients and the SOD1G93A mouse model of ALS were quantified for their expression of Wnt1, Wnt3a, Wnt5a, Wnt7a, and beta-catenin.

RESULTS: All four Wnt isoforms were expressed in most axon profiles in all human EOMs. Significantly fewer were positive for Wnt1, Wnt3a, and Wnt7a in the human limb muscles. Similar differential patterns in Wnt myofiber expression was also seen, except for Wnt7a, where expression was elevated. In the SOD1G93A mouse, all 4 Wnt isoforms were significantly decreased in the neuromuscular junctions at the terminal stage compared to age matched controls. Beta-catenin was activated in a subset of myofibers in EOM and limb muscle in all patients.

CONCLUSIONS: The differences in Wnt expression in EOM and limb muscle, particularly at the neuromuscular junction level, suggest that they play a role in the pathophysiology of ALS. Collectively, the data support a role for Wnt signaling in the preservation of the EOM in ALS and their dysregulation and the subsequent development of pathology in the ALS limb muscles.

Place, publisher, year, edition, pages
ARVO, The Association for Reserach in Vision and Ophthalmology, 2014
Keywords
extraocular muscles, Wnt, neuromuscular junctions, amyotrophic lateral sclerosis, beta-catenin, skeletal muscle, SOD1(G93A) mice
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-91978 (URN)10.1167/iovs.14-14886 (DOI)000343146900003 ()25125606 (PubMedID)2-s2.0-84908099176 (Scopus ID)
Available from: 2014-08-20 Created: 2014-08-20 Last updated: 2023-03-24Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-9255-0517

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