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Is functional hypertrophy and specific force coupled with the addition of myonuclei at the single muscle fiber level?
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. (Professor Lars Larsson group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
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2012 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 3, 1077-1085 p.Article in journal (Refereed) Published
Abstract [en]

Muscle force is typically proportional to muscle size, resulting in constant force normalized to muscle fiber cross-sectional area (specific force). Mice overexpressing insulin-like growth factor-1 (IGF-1) exhibit a proportional gain in muscle force and size, but not the myostatin-deficient mice. In an attempt to explore the role of the cytoplasmic volume supported by individual myonuclei [myonuclear domain (MND) size] on functional capacity of skeletal muscle, we have investigated specific force in relation to MND and the content of the molecular motor protein, myosin, at the single muscle fiber level from myostatin-knockout (Mstn(-/-)) and IGF-1-overexpressing (mIgf1(+/+)) mice. We hypothesize that the addition of extra myonuclei is a prerequisite for maintenance of specific force during muscle hypertrophy. A novel algorithm was used to measure individual MNDs in 3 dimensions along the length of single muscle fibers from the fast-twitch extensor digitorum longus and the slow-twitch soleus muscle. A significant effect of the size of individual MNDs in hypertrophic muscle fibers on both specific force and myosin content was observed. This effect was muscle cell type specific and suggested there is a critical volume individual myonuclei can support efficiently. The large MNDs found in fast muscles of Mstn(-/-) mice were correlated with the decrement in specific force and myosin content in Mstn(-/-) muscles. Thus, myostatin inhibition may not be able to maintain the appropriate MND for optimal function.-Qaisar, R., Renaud, G., Morine, K., Barton, E. R., Sweeney, H. L., Larsson, L. Is functional hypertrophy and specific force coupled with the addition of myonuclei at the single muscle fiber level?

Place, publisher, year, edition, pages
2012. Vol. 26, no 3, 1077-1085 p.
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-166951DOI: 10.1096/fj.11-192195ISI: 000300949300012PubMedID: 22125316OAI: oai:DiVA.org:uu-166951DiVA: diva2:479163
Available from: 2012-01-17 Created: 2012-01-17 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Myonuclear Organization and Regulation of Muscle Contraction in Single Muscle Fibres: Effects of Ageing, Gender, Species, Endocrine Factors and Muscle Size
Open this publication in new window or tab >>Myonuclear Organization and Regulation of Muscle Contraction in Single Muscle Fibres: Effects of Ageing, Gender, Species, Endocrine Factors and Muscle Size
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The skeletal muscle fibre is a syncitium where each myonucleus regulates the gene products in a finite volume of cytoplasm i.e., the myonuclear domain (MND). A novel image analysis algorithm applied to confocal images, analyzing MND size and myonuclear spatial distribution in 3-dimensions in single skeletal muscle fibres has been used in this project. The goal was to explore the modulation of myonuclei count and MND size in response to muscle adaptation processes. The effects of ageing, gender, hormones, muscle hypertrophy and body size were investigated on MND size.

A strong linear relationship was found between MND size and body size in the muscle fibres from mammals representing a 100,000-fold difference in body size. Independent of species, MND size was highly dependent on MyHC isoform type and mitochondrial contents of skeletal muscle fibres. In hypertrophic mice, a significant effect of MND size on specific force and myosin content was observed. This effect was muscle fibre type-specific and shows that the bigger MNDs in fast-twitch EDL muscle fibres are optimally tuned for force production while smaller MNDs in slow-twitch soleus muscle fibres have a much more dynamic range of hypertrophy without functional compromise. This indicates a critical volume individual myonuclei can support efficiently for a proportional gain in muscle fibre force and size. In human muscle fibres, spatial organization of myonuclei was affected by both ageing and MyHC isoform expression. In fibres expressing type I MyHC isoform, an increased MND size variability and myonuclear aggregates were observed in old age although average MND size was unchanged. In contrast, in type IIa fibres, the average MND size was smaller reflecting smaller size of muscle fibres. Those changes may influence the transcriptional activity per myonucleus and/or local cooperatively of myonuclei in a gender and muscle fibre-type specific manner. Finally, hormone replacement therapy was shown to negate menopause-related functional impairment in skeletal muscle fibres. The positive effect on force was due to quantitative effect in fibres expressing fast myosin isoform while the effect was both quantitative and qualitative in fibres expressing slow myosin isoform. The effect on MND size was fibre type dependent and was achieved by significantly reducing domain size in slow- but not the fast-twitch muscle fibres.

Together, our data suggest that modulation of myonuclei count and MND size is a mechanism contributing to remodelling of skeletal muscle in muscle adaptation process. These findings should be considered when developing therapeutic approaches towards restoring muscle mass and strength in muscle wasting conditions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 737
Keyword
single muscle cells, muscle nuclei, specific force, species, hypertrophy, mammals, ageing, gender
National Category
Neurosciences
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-167723 (URN)978-91-554-8264-0 (ISBN)
Public defence
2012-03-15, Hedstrandsalen, Ingång 70, bv,AS Akademiska sjukhuset, Uppsala, 09:15 (English)
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Available from: 2012-02-28 Created: 2012-02-01 Last updated: 2012-03-01Bibliographically approved

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