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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, A.; Flasskamp, Hannah; Ray, Steve; Dash, Philip R.; Sandri, Marco; Patel, Ketan

Authors

Henry Collins-Hooper

Philip R. Dash

Hannah Flasskamp

Keith Foster

Raymond Macharia

Ketan Patel

Steve Ray

Marco Sandri

Roberta Sartori

Korntip Visanuvimol

H. Collins-Hooper

R. Sartori

R. Macharia

K. Visanuvimol

K. Foster

H. Flasskamp

S. Ray

P. R. Dash

M. Sandri

K. Patel

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.

Journal Article Type Article
Publication Date Sep 1, 2014
Journal Journals of gerontology : series A
Print ISSN 1079-5006
Electronic ISSN 1758-535X
Publisher Oxford University Press (OUP)
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
Publisher URL http://biomedgerontology.oxfordjournals.org/content/69/9/1049
Copyright Statement © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.
Additional Information Copy of article first published in: Journals of gerontology : series A, 2014, v.69, issue 9.

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