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Myonuclear Organization and Regulation of Muscle Contraction in Single Muscle Fibres: Effects of Ageing, Gender, Species, Endocrine Factors and Muscle Size
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. (Professor Lars Larsson group)
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 [en]
single muscle cells, muscle nuclei, specific force, species, hypertrophy, mammals, ageing, gender
National Category
Neurosciences
Research subject
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-167723ISBN: 978-91-554-8264-0 (print)OAI: oai:DiVA.org:uu-167723DiVA: diva2:487900
Public defence
2012-03-15, Hedstrandsalen, Ingång 70, bv,AS Akademiska sjukhuset, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-02-28 Created: 2012-02-01 Last updated: 2012-03-01Bibliographically approved
List of papers
1. Myonuclear domain size and myosin isoform expression in muscle fibres from mammals representing a 100 000-fold difference in body size
Open this publication in new window or tab >>Myonuclear domain size and myosin isoform expression in muscle fibres from mammals representing a 100 000-fold difference in body size
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2009 (English)In: Experimental Physiology, ISSN 0958-0670, E-ISSN 1469-445X, Vol. 94, no 1, 117-129 p.Article in journal (Refereed) Published
Abstract [en]

This comparative study of myonuclear domain (MND) size in mammalian species representing a 100 000-fold difference in body mass, ranging from 25 g to 2500 kg, was undertaken to improve our understanding of myonuclear organization in skeletal muscle fibres. Myonuclear domain size was calculated from three-dimensional reconstructions in a total of 235 single muscle fibre segments at a fixed sarcomere length. Irrespective of species, the largest MND size was observed in muscle fibres expressing fast myosin heavy chain (MyHC) isoforms, but in the two smallest mammalian species studied (mouse and rat), MND size was not larger in the fast-twitch fibres expressing the IIA MyHC isofom than in the slow-twitch type I fibres. In the larger mammals, the type I fibres always had the smallest average MND size, but contrary to mouse and rat muscles, type IIA fibres had lower mitochondrial enzyme activities than type I fibres. Myonuclear domain size was highly dependent on body mass in the two muscle fibre types expressed in all species, i.e. types I and IIA. Myonuclear domain size increased in muscle fibres expressing both the β/slow (type I; r= 0.84, P < 0.001) and the fast IIA MyHC isoform (r= 0.90; P < 0.001). Thus, MND size scales with body size and is highly dependent on muscle fibre type, independent of species. However, myosin isoform expression is not the sole protein determining MND size, and other protein systems, such as mitochondrial proteins, may be equally or more important determinants of MND size.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-87940 (URN)10.1113/expphysiol.2008.043877 (DOI)000261961800014 ()18820003 (PubMedID)
Available from: 2009-01-15 Created: 2009-01-15 Last updated: 2017-12-14Bibliographically approved
2. Is functional hypertrophy and specific force coupled with the addition of myonuclei at the single muscle fiber level?
Open this publication in new window or tab >>Is functional hypertrophy and specific force coupled with the addition of myonuclei at the single muscle fiber level?
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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?

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-166951 (URN)10.1096/fj.11-192195 (DOI)000300949300012 ()22125316 (PubMedID)
Available from: 2012-01-17 Created: 2012-01-17 Last updated: 2017-12-08Bibliographically approved
3. Effects of aging and gender on the spatial organization of nuclei in single human skeletal muscle cells
Open this publication in new window or tab >>Effects of aging and gender on the spatial organization of nuclei in single human skeletal muscle cells
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2010 (English)In: Aging Cell, ISSN 1474-9718, E-ISSN 1474-9726, Vol. 9, no 5, 685-697 p.Article in journal (Refereed) Published
Abstract [en]

The skeletal muscle fibre is a syncitium where each myonucleus regulates the gene products in a finite volume of the cytoplasm, i.e., the myonuclear domain (MND). We analysed aging- and gender-related effects on myonuclei organization and the MND size in single muscle fibres from six young (21–31 years) and nine old men (72–96 years), and from six young (24–32 years) and nine old women (65–96 years), using a novel image analysis algorithm applied to confocal images. Muscle fibres were classified according to myosin heavy chain (MyHC) isoform expression. Our image analysis algorithm was effective in determining the spatial organization of myonuclei and the distribution of individual MNDs along the single fibre segments. Significant linear relations were observed between MND size and fibre size, irrespective age, gender and MyHC isoform expression. The spatial organization of individual myonuclei, calculated as the distribution of nearest neighbour distances in 3D, and MND size were affected in old age, but changes were dependent on MyHC isoform expression. In type I muscle fibres, average NN-values were lower and showed an increased variability in old age, reflecting an aggregation of myonuclei in old age. Average MND size did not change in old age, but there was an increased MND size variability. In type IIa fibres, average NN-values and MND sizes were lower in old age, reflecting the smaller size of these muscle fibres in old age. It is suggested that these changes have a significant impact on protein synthesis and degradation during the aging process.

Keyword
aging, human skeletal muscle, myonuclear domain, 3D imaging
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-139870 (URN)10.1111/j.1474-9726.2010.00594.x (DOI)000281897400003 ()20633000 (PubMedID)
Available from: 2010-12-30 Created: 2010-12-30 Last updated: 2017-12-11Bibliographically approved
4. Contractile function and myonuclear organization in single fibers from monozygotic female twins discordant for hormone replacement therapy
Open this publication in new window or tab >>Contractile function and myonuclear organization in single fibers from monozygotic female twins discordant for hormone replacement therapy
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(English)Manuscript (preprint) (Other academic)
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-166952 (URN)
Available from: 2012-01-17 Created: 2012-01-17 Last updated: 2012-03-01

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