Muscle hypertrophy driven by myostatin blockade does not require stem/precursor-cell activity

Amthor, Helge; Otto, Anthony; Vulin, Adeline; Rochat, Anne; Dumonceaux, Julie; Garcia, Luis; Mouisel, Etienne; Hourdé, Christophe; Macharia, Raymond; Friedrichs, Melanie; Relaix, Fre?de?ric; Zammit, Peter S.; Matsakas, Antonios; Patel, Ketan; Partridge, Terence

Abstract

Myostatin, a member of the TGF-β family, has been identified as a powerful inhibitor of muscle growth. Absence or blockade of myostatin induces massive skeletal muscle hypertrophy that is widely attributed to proliferation of the population of muscle fiber-associated satellite cells that have been identified as the principle source of new muscle tissue during growth and regeneration. Postnatal blockade of myostatin has been proposed as a basis for therapeutic strategies to combat muscle loss in genetic and acquired myopathies. But this approach, according to the accepted mechanism, would raise the threat of premature exhaustion of the pool of satellite cells and eventual failure of muscle regeneration. Here, we show that hypertrophy in the absence of myostatin involves little or no input from satellite cells. Hypertrophic fibers contain no more myonuclei or satellite cells and myostatin had no significant effect on satellite cell proliferation in vitro, while expression of myostatin receptors dropped to the limits of detectability in postnatal satellite cells. Moreover, hypertrophy of dystrophic muscle arising from myostatin blockade was achieved without any apparent enhancement of contribution of myonuclei from satellite cells. These findings contradict the accepted model of myostatin-based control of size of postnatal muscle and reorient fundamental investigations away from the mechanisms that control satellite cell proliferation and toward those that increase myonuclear domain, by modulating synthesis and turnover of structural muscle fiber proteins. It predicts too that any benefits of myostatin blockade in chronic myopathies are unlikely to impose any extra stress on the satellite cells.

Citation

Amthor, H., Otto, A., Vulin, A., Rochat, A., Dumonceaux, J., Garcia, L., Mouisel, E., Hourdé, C., Macharia, R., Friedrichs, M., Relaix, F., Zammit, P. S., Matsakas, A., Patel, K., & Partridge, T. (2009). Muscle hypertrophy driven by myostatin blockade does not require stem/precursor-cell activity. Proceedings of the National Academy of Sciences of the United States of America, 106(18), 7479-7484. https://doi.org/10.1073/pnas.0811129106

• Acceptance Date: Mar 9, 2009
• Online Publication Date: Apr 21, 2009
• Publication Date: May 5, 2009
• Deposit Date: Nov 13, 2014
• Publicly Available Date: Nov 13, 2014
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Print ISSN: 0027-8424
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 106
• Issue: 18
• Pages: 7479-7484
• DOI: https://doi.org/10.1073/pnas.0811129106
• Keywords: Muscle growth, Muscular dystrophy, TGF-beta, Muscle stem cells, Myonuclear domain
• Public URL: https://hull-repository.worktribe.com/output/469399
• Publisher URL: http://www.pnas.org/content/106/18/7479?tab=author-info
• Additional Information: Copy of article: Helge Amthor, Anthony Otto, Adeline Vulin, Anne Rochat, Julie Dumonceaux, Luis Garcia, Etienne Mouisel, Christophe Hourdé, Raymond Macharia, Melanie Friedrichs, Frederic Relaix, Peter S. Zammit, Antonios Matsakas, Ketan Patel, and Terence Partridge Muscle hypertrophy driven by myostatin blockade does not require stem/precursor-cell activity PNAS 2009 106 (18) 7479-7484; published ahead of print April 21, 2009, doi:10.1073/pnas.0811129106
• Contract Date: Nov 13, 2014