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IGF-1 Regulation of Skeletal Muscle Hypertrophy and Atrophy

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IGFs:Local Repair and Survival Factors Throughout Life Span

Part of the book series: Research and Perspectives in Endocrine Interactions ((RPEI))

Abstract

Insulin-like growth factor 1 (IGF-1) can induce skeletal muscle hypertrophy, defined as an increase in skeletal muscle mass. Hypertrophy occurs as a result of an increase in the size, as opposed to the number, of pre-existing skeletal muscle fibers. IGF-1's pro-hypertrophy activity comes predominantly through its ability to activate the Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Akt is a serine-threonine protein kinase that can induce protein synthesis and can block the transcriptional upregulation of key mediators of skeletal muscle atrophy, the E3 ubiquitin ligases MuRF1 and MAFbx (also called Atrogin-1), by phosphorylating and thereby inhibiting the nuclear translocation of the FOXO (also called “forkhead”) family of transcription factors. Once phosphorylated by Akt, the FOXOs are excluded from the nucleus, and upregulation of MuRF1 and MAFbx is blocked. MuRF1 and MAFbx mediate atrophy by ubiquitinating particular protein substrates, causing them to undergo degradation by the proteasome. MuRF1's substrates include several components of the sarcomeric thick filament, including Myosin Heavy Chain (MyHC). Thus, by blocking MuRF1 activation, IGF-1 helps prevent the breakdown of the thick filament under atrophy conditions.

IGF-1 also can dominantly inhibit the effects of a secreted protein called myostatin, which is a member of the TGFβ family of proteins. Deletion or inhibition of myostatin causes an increase in skeletal muscle size, because myostatin acts to both inhibit myoblast differentiation and block the Akt pathway. Thus by blocking myostatin, IGF-1 stimulates differentiation and protein synthesis by this distinct mechanism. Myostatin induces the phosphorylation and activation of the transcription factors of Smad2 and Smad3, downstream of the ActRII (Activin Receptor type II)/Alk (Activin Receptor-like kinase) receptor complex. Other TGFβ-like molecules can also block differentiation, including TGF-b1, GDF-11, activinA, BMP-2 and BMP-7. As mentioned, myostatin also downregulates the Akt/mTOR/p70S6 protein synthesis pathway, which mediates both differentiation in myoblasts and hypertrophy in myotubes. Blockade of the Akt/mTOR pathway, using siRNA to RAPTOR, a component of “TORC1” (TOR signaling Complex 1), increases myostatin-induced phosphorylation of Smad2, which establishes a “feed-forward mechanism”, since myostatin can downregulate TORC1, and this downregulation in turn amplifies myostatin signaling. Blockade of RAPTOR also facilitates myostatin's inhibition of muscle differentiation. When added to post-differentiated myotubes, myostatin causes a decrease in their diameter; however, this decrease does not happen through the normal “atrophy pathway.” Rather than causing upregulation of the E3 ubiquitin ligases MuRF1 and MAFbx, which have previously been shown to mediate skeletal muscle atrophy, myostatin decreases expression of these atrophy markers in differentiated myotubes, as well as other genes normally upregulated during differentiation, such as MyoD and myogenin. These findings demonstrate that myostatin signaling acts by blocking genes induced during differentiation, even in a myotube, as opposed to activating the distinct “atrophy program.”

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Acknowledgments

Thank you to Drs. M. Fishman, B. Richardson, A. Mackenzie, as well as the rest of the Novartis Community, for their enthusiastic support and input. This work, in particular referenced studies, was performed in large part by A.U. Trendelenburg, B. Clarke, and E. Latres.

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  1. Novartis Institutes for BioMedical Research Inc., 100 Technology Square room 4210, Cambridge, MA, 02139, USA

    David J. Glass

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  1. Chapel Hill, University of North Carolina, Burnett-Womack Hall 8024, Chapel Hill, 27599-7170, U.S.A.

    David Clemmons

  2. Lab. Endocrine Physiology, National Inst. Med. Research, The Ridgeway, London, NW7 1AA, United Kingdom

    Iain C.A.F. Robinson

  3. Recherche Therapeutique, Fondation IPSEN pour la, quai George Gorse 65, Boulogne Billancourt Cedex, 92650, France

    Yves Christen

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Glass, D.J. (2010). IGF-1 Regulation of Skeletal Muscle Hypertrophy and Atrophy. In: Clemmons, D., Robinson, I., Christen, Y. (eds) IGFs:Local Repair and Survival Factors Throughout Life Span. Research and Perspectives in Endocrine Interactions. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-04302-4_7

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