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    Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin

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    Author
    Winbanks, CE; Weeks, KL; Thomson, RE; Sepulveda, PV; Beyer, C; Qian, H; Chen, JL; Allen, JM; Lancaster, GI; Febbraio, MA; ...
    Date
    2012-06-25
    Source Title
    JOURNAL OF CELL BIOLOGY
    Publisher
    ROCKEFELLER UNIV PRESS
    University of Melbourne Author/s
    Gregorevic, Paul; Thomson, Rachel; Qian, Hongwei
    Affiliation
    Physiology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Winbanks, C. E., Weeks, K. L., Thomson, R. E., Sepulveda, P. V., Beyer, C., Qian, H., Chen, J. L., Allen, J. M., Lancaster, G. I., Febbraio, M. A., Harrison, C. A., McMullen, J. R., Chamberlain, J. S. & Gregorevic, P. (2012). Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin. JOURNAL OF CELL BIOLOGY, 197 (7), pp.997-1008. https://doi.org/10.1083/jcb.201109091.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/32830
    DOI
    10.1083/jcb.201109091
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384410
    Description

    C1 - Journal Articles Refereed

    Abstract
    Follistatin is essential for skeletal muscle development and growth, but the intracellular signaling networks that regulate follistatin-mediated effects are not well defined. We show here that the administration of an adeno-associated viral vector expressing follistatin-288aa (rAAV6:Fst-288) markedly increased muscle mass and force-producing capacity concomitant with increased protein synthesis and mammalian target of rapamycin (mTOR) activation. These effects were attenuated by inhibition of mTOR or deletion of S6K1/2. Furthermore, we identify Smad3 as the critical intracellular link that mediates the effects of follistatin on mTOR signaling. Expression of constitutively active Smad3 not only markedly prevented skeletal muscle growth induced by follistatin but also potently suppressed follistatin-induced Akt/mTOR/S6K signaling. Importantly, the regulation of Smad3- and mTOR-dependent events by follistatin occurred independently of overexpression or knockout of myostatin, a key repressor of muscle development that can regulate Smad3 and mTOR signaling and that is itself inhibited by follistatin. These findings identify a critical role of Smad3/Akt/mTOR/S6K/S6RP signaling in follistatin-mediated muscle growth that operates independently of myostatin-driven mechanisms.
    Keywords
    Cell Physiology; Skeletal System and Disorders (incl. Arthritis)

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