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Satellite cells in human skeletal muscle: molecular identification quantification and function
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. (Muskelgruppen)
2009 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Satellitceller i human skelettmuskulatur : molekylär identifiering, kvantifiering och funktion (Swedish)
Abstract [en]

Skeletal muscle satellite cells located between the plasma membrane and the basal lamina of muscle fibres, could for many years, only be studied in situ by electron microscopy. The introduction of immunohistochemistry and the discovery of molecular markers of satellite cells then made them accessible for light microscopic studies and a wealth of information is today available. Satellite cells are myogenic stem cells that can be activated from a quiescent state to proliferate for self-renewal or differentiate into myogenic cells. The satellite cells are involved in muscle growth during fetal and postnatal development and play a key role in repair and regeneration of damaged muscle fibres. The satellite cells are also essential for muscle fibre hypertrophy and maintenance of muscle mass in the adult. When the present thesis was initiated, studies on satellite cells in human skeletal muscle relied on the neuronal cell adhesion molecule (NCAM) as a marker for satellite cell identification. The results from different studies varied markedly. Therefore the aims of the present thesis were i) to develop a highly reliable method using light microscopy for satellite cell identification and quantification in biopsies of human skeletal muscle in normal and pathological conditions. A molecular marker for the myofibre basal lamina or plasma membrane to enhance the reliability of myonuclei and satellite cell identification were to be included. Furthermore unbiased morphometric methods should be used in the quantification process. ii) to evaluate which molecular markers which had been described for satellite cell and stem cell identification in different cell states (quiescence, activated or differentiated) are the most useful for studies on human skeletal muscle. iii) to further explore the function and heterogeneity of satellite cells with respect to different markers in human skeletal muscle by studying the effects of strength-training, intake of anabolic substances and pathological conditions.

A new immunofluorescence method was developed where in the same tissue section, two satellite cell markers, the basal lamina and nuclei were monitored. From the evaluation of different markers it was found that both NCAM and Pax7 identified the majority of satellite cells but that both markers were needed for reliable identification. The members of the myogenic regulatory family were evaluated and by using the new method MyoD and myogenin were found to be useful markers to identify activated and differentiated satellite cells. Upon re-examination of biopsies from power-lifters, power-lifters using anabolic substances and untrained subjects it was observed that the new results on satellite cell frequency were significantly different from those obtained when using staining for NCAM and nuclei alone. In addition three subtypes of satellite cells (94.4% NCAM+/Pax7+, 4.2% NCAM+/Pax7 and 1.4% NCAM/Pax7+) were observed. Thus the multiple marker method gave more information about satellite cells heterogeneity in human muscle and we propose that this is more reliable than previous methods. Low numbers of MyoD or myogenin stained satellite cells were observed in both untrained and strength trained subjects. Other markers such as DLK1/FA1, a member of the EGF-like family and c-Met, the receptor for hepatocyte growth factor showed that satellite cell heterogeneity in human muscle is far greater than previously shown. Furthermore, new evidence is presented for so called fibre splitting observed in hypertrophic muscle fibres to be due to defect regeneration of partially damaged fibres.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2009. , 56 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1313
Keyword [en]
satellite cell markers, NCAM, Pax7, MyoD, myogenin, DLK1/FA1, c-Met, human skeletal muscle, immunohistochemistry, muscle growth, muscle hypertrophy
National Category
Cell and Molecular Biology
Research subject
Human Anatomy
Identifiers
URN: urn:nbn:se:umu:diva-29817ISBN: 978-91-7264-900-2 (print)OAI: oai:DiVA.org:umu-29817DiVA: diva2:278182
Public defence
2009-12-18, Biologihuset, sal BiA201, Umeå Universitet, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2009-12-01 Created: 2009-11-24 Last updated: 2011-04-07Bibliographically approved
List of papers
1. Satellite cells and training in the elderly.
Open this publication in new window or tab >>Satellite cells and training in the elderly.
Show others...
2003 (English)In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 13, no 1, 48-55 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Blackwell Munksgaard, 2003
Keyword
muscle, training, ageing, satellite cells, muscle fibres, telomeres
National Category
Cell and Molecular Biology Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Human Anatomy
Identifiers
urn:nbn:se:umu:diva-29797 (URN)10.1034/j.1600-0838.2003.20285.x (DOI)12535317 (PubMedID)
Available from: 2009-11-24 Created: 2009-11-23 Last updated: 2017-12-12Bibliographically approved
2. New multiple labelling method for improved satellite cell identification in human muscle: application to a cohort of power-lifters and sedentary men.
Open this publication in new window or tab >>New multiple labelling method for improved satellite cell identification in human muscle: application to a cohort of power-lifters and sedentary men.
2009 (English)In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 132, no 2, 141-57 p.Article in journal (Refereed) Published
Abstract [en]

Presently applied methods to identify and quantify human satellite cells (SCs) give discrepant results. We introduce a new immunofluorescence method that simultaneously monitors two SC markers (NCAM and Pax7), the basal lamina and nuclei. Biopsies from power-lifters, power-lifters using anabolic substances and untrained subjects were re-examined. Significantly different results from those with staining for NCAM and nuclei were observed. There were three subtypes of SCs; NCAM(+)/Pax7(+) (94%), NCAM(+)/Pax7(-) (4%) and NCAM(-)/Pax7(+) (1%) but large individual variability existed. The proportion of SCs per nuclei within the basal lamina of myofibres (SC/N) was similar for all groups reflecting a balance between the number of SCs and myonuclei to maintain homeostasis. We emphasise that it is important to quantify both SC/N and the number of SCs per fibre. Our multiple marker method is more reliable for SC identification and quantification and can be used to evaluate other markers of muscle progenitor cells.

Place, publisher, year, edition, pages
Springer-Verlag, 2009
Keyword
Stem cells, NCAM, Pax7, Trapezius muscle, Immunofluorescense, Anabolic steroids
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:umu:diva-29796 (URN)10.1007/s00418-009-0606-0 (DOI)19484472 (PubMedID)
Available from: 2009-11-23 Created: 2009-11-23 Last updated: 2017-12-12Bibliographically approved
3. Satellite cell heterogeneity with respect to expression of MyoD, myogenin, Dlk1 and c-Met in human skeletal muscle: application to a cohort of power lifters and sedentary men
Open this publication in new window or tab >>Satellite cell heterogeneity with respect to expression of MyoD, myogenin, Dlk1 and c-Met in human skeletal muscle: application to a cohort of power lifters and sedentary men
2010 (English)In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 134, no 4, 371-385 p.Article in journal (Refereed) Published
Abstract [en]

Human satellite cells (SCs) are heterogeneous with respect to markers for their identification in the niche between the muscle fibre plasma membrane and its basal lamina. We have previously shown that, in biopsies from highly competitive power lifters, power lifters with long-term use of anabolic steroids and a population of healthy sedentary men, antibodies against the neuronal cell adhesion molecule (NCAM) and the paired box transcription factor Pax7 together label 94% of the SCs, NCAM alone labels 4% and Pax7 alone labels 1%. In the present study, we have further studied these biopsies with four markers related to SC activation and differentiation. Our study unequivocally shows that staining for MyoD and myogenin are present in nuclei of SCs and of myoblasts and myotubes in areas of muscle fibre regeneration. Staining for c-Met was observed in a proportion of Pax7+ SCs. However, widespread labelling of the sarcolemma precluded the quantification of c-Met+/Pax7+ SCs and the use of c-Met as a reliable SC marker. Pax7+ SCs labelled by anti-Delta like1 (Dlk1) were present in all samples but in variable proportions, whereas muscle progenitor cells related to repair were Dlk1⁻. Staining for Dlk1 was also observed in Pax7⁻ interstitial cells and in the cytoplasm of some small muscle fibres. Interestingly, the proportion of Dlk1+/Pax7+ SCs was significantly different between the groups of power lifters. Thus, our study confirms that human SCs show marked heterogeneity and this is discussed in terms of SC activation, myonuclei turnover, muscle fibre growth and muscle fibre damage and repair.

Keyword
Skeletal muscle satellite cells, Myogenic regulatory factors, Pax7, Dlk1/FA1, Strength training, Anabolic steroids
Identifiers
urn:nbn:se:umu:diva-42310 (URN)10.1007/s00418-010-0743-5 (DOI)000282974600008 ()20878332 (PubMedID)
Available from: 2011-04-07 Created: 2011-04-07 Last updated: 2017-12-11Bibliographically approved
4. Hypertrophic muscle fibers with fissures in power-lifters; fiber splitting or defect regeneration?
Open this publication in new window or tab >>Hypertrophic muscle fibers with fissures in power-lifters; fiber splitting or defect regeneration?
2006 (English)In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 126, no 4, 409-417 p.Article in journal (Refereed) Published
Abstract [en]

Power-lifters have hypertrophic muscle fibers with fissures seen in cross-sections, called as fiber splitting.Whether this phenomenon is due to real splitting or defective regeneration has not been settled. To elucidate this matter,we have examined biopsies from the trapezius and vastus lateralis of power lifters (P group) and power lifters self-administrating anabolic steroids (PAS group). For this purpose, immunohistochemical staining of serial cross -sections was used. The PAS group had significantly more fibers with fissures than the P group in the vastus lateralis (1.2%+/-0.95% vs 0.35+/-0.34, P < 0.05) but not in the trapezius muscle (1.7% in both groups). Serial sections revealed that the fibers with fissures changed their profile profoundly over short distances. Some such fibers had a mature staining profile, whereas other fibers indicated recent degeneration and/or regeneration. Activation of satellite cells and formation of aberrant segments were also evident. We conclude that the so-called split fibers are due to defect regeneration. Some fibers with fissures are the results of old events of segmental muscle fiber damage, whereas the others reflect an ongoing process. The normal regenerative process is most likely disturbed in power-lifters by their continuous training with repeated high mechanical stress on the muscles.

Keyword
Adult, Anabolic Agents/administration & dosage, Humans, Hypertrophy, Immunohistochemistry, Male, Muscle Fibers/*pathology/*physiology, Muscle; Skeletal/drug effects/ultrastructure, Regeneration, Self Administration, Steroids/administration & dosage, Weight Lifting
Identifiers
urn:nbn:se:umu:diva-12683 (URN)10.1007/s00418-006-0176-3 (DOI)16625366 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved

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