Propeptide-mediated inhibition of myostatin increases muscle mass through inhibiting proteolytic pathways in aged mice

Collins-Hooper, H.; Sartori, R.; Macharia, R.; Visanuvimol, K.; Foster, K.; Flasskamp, H.; Ray, S.; Dash, P. R.; Sandri, M.; Patel, K.; Collins-Hooper, Henry; Sartori, Roberta; Macharia, Raymond; Visanuvimol, Korntip; Foster, Keith; Matsakas, Antonios; Flasskamp, Hannah; Ray, Steve; Dash, Philip R.; Sandri, Marco; Patel, Ketan

Abstract

Mammalian aging is accompanied by a progressive loss of skeletal muscle, a process called sarcopenia. Myostatin, a secreted member of the transforming growth factor-β family of signaling molecules, has been shown to be a potent inhibitor of muscle growth. Here, we examined whether muscle growth could be promoted in aged animals by antagonizing the activity of myostatin through the neutralizing activity of the myostatin propeptide. We show that a single injection of an AAV8 virus expressing the myostatin propeptide induced an increase in whole body weights and all muscles examined within 7 weeks of treatment. Our cellular studies demonstrate that muscle enlargement was due to selective fiber type hypertrophy, which was accompanied by a shift toward a glycolytic phenotype. Our molecular investigations elucidate the mechanism underpinning muscle hypertrophy by showing a decrease in the expression of key genes that control ubiquitin-mediated protein breakdown. Most importantly, we show that the hypertrophic muscle that develops as a consequence of myostatin propeptide in aged mice has normal contractile properties. We suggest that attenuating myostatin signaling could be a very attractive strategy to halt and possibly reverse age-related muscle loss.

Citation

Collins-Hooper, H., Sartori, R., Macharia, R., Visanuvimol, K., Foster, K., Matsakas, A., Flasskamp, H., Ray, S., Dash, P. R., Sandri, M., & Patel, K. (2014). Propeptide-mediated inhibition of myostatin increases muscle mass through inhibiting proteolytic pathways in aged mice. The journals of gerontology. Series A, Biological sciences and medical sciences, 69(9), 1049-1059. https://doi.org/10.1093/gerona/glt170

• Journal Article Type: Article
• Acceptance Date: Sep 16, 2013
• Online Publication Date: Jan 11, 2014
• Publication Date: Sep 1, 2014
• Deposit Date: May 21, 2015
• Publicly Available Date: May 21, 2015
• Journal: Journals of gerontology : series A
• Print ISSN: 1079-5006
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 69
• Issue: 9
• Pages: 1049-1059
• DOI: https://doi.org/10.1093/gerona/glt170
• Keywords: Muscle, Myostatin, Aging, Mouse, Sarcopenia
• Public URL: https://hull-repository.worktribe.com/output/374119
• Publisher URL: http://biomedgerontology.oxfordjournals.org/content/69/9/1049
• Additional Information: Copy of article first published in: Journals of gerontology : series A, 2014, v.69, issue 9.
• Contract Date: May 21, 2015