Review
Skeletal muscle hypertrophy and atrophy signaling pathways

https://doi.org/10.1016/j.biocel.2005.04.018Get rights and content

Abstract

Skeletal muscle hypertrophy is defined as an increase in muscle mass, which in the adult animal comes as a result of an increase in the size, as opposed to the number, of pre-existing skeletal muscle fibers. The protein growth factor insulin-like growth factor 1 (IGF-1) has been demonstrated to be sufficient to induce skeletal muscle hypertrophy. Over the past few years, signaling pathways which are activated by IGF-1, and which are responsible for regulating protein synthesis pathways, have been defined. More recently, it has been show that IGF-1 can also block the transcriptional upregulation of key mediators of skeletal muscle atrophy, the ubiquitin-ligases MuRF1 and MAFbx (also called Atrogin-1). Further, it has been demonstrated recently that activation of the NF-κB transcription pathway, activated by cachectic factors such as TNFα, is sufficient to induce skeletal muscle atrophy, and this atrophy occurs in part via NF-κB-mediated upregulation of MuRF1. Further work has demonstrated a trigger for MAFbx expression upon treatment with TNFα—the p38 MAPK pathway. This review will focus on the recent progress in the understanding of molecular signalling, which governs skeletal muscle atrophy and hypertrophy, and the known instances of cross-regulation between the two systems.

Section snippets

Protein synthesis pathways downstream of IGF-1

An increase in weight-bearing by a muscle, as seen in models of muscle hypertrophy such as “compensatory hypertrophy” as well as agents that induce hypertrophy such as IGF-1, induce an increase in muscle mass by stimulating the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, resulting in the downstream activation of targets which are required for protein synthesis (Bodine, Stitt, et al., 2001; Rommel et al., 2001) (Fig. 1). Overload-induced muscle hypertrophy may lead to activation of the

Hypertrophy mediators downstream of PI3K and Akt: the Akt/mTOR pathway

Experiments in Drosophila helped to define a pathway downstream of PI3K and Akt, which can control cell size (Fig. 1). Negative genetic perturbations of IRS-1 (Bohni et al., 1999), PI3K (Leevers, Weinkove, MacDougall, Hafen, & Waterfield, 1996), the Drosophila homolog of the mammalian target of rapamycin (mTOR, also known as FRAP or RAFT-1) (Zhang, Stallock, Ng, Reinhard, & Neufeld, 2000) as well as of p70S6 Kinase (Montagne et al., 1999) (p70S6K) each resulted in decreases in cell size.

A second hypertrophy mediator downstream of PI3K and Akt: GSK3β

Glycogen synthase kinase 3 beta, GSK3β, is a distinct substrate of Akt that has been shown to modulate hypertrophy. GSK3β activity is inhibited by Akt phosphorylation (Cross, Alessi, Cohen, Andjelkovich, & Hemmings, 1995). Expression of a dominant negative, kinase inactive form of GSK3β-induces dramatic hypertrophy in skeletal myotubes (Rommel et al., 2001), as does pharmacologic inhibition of GSK3β (Vyas, Spangenburg, Abraha, Childs, & Booth, 2002). In cardiac hypertrophy, GSK3β

Skeletal muscle atrophy occurs in part via induction of distinct E3 ubiquitin ligases

One might wonder whether skeletal muscle atrophy might simply be the converse of hypertrophy. Indeed, the hypertrophy-inducing Akt protein synthesis pathways have been shown to be inhibited in a burn model of atrophy (Sugita et al., 2005), and there is a distinct set of genes, which are inversely regulated by hypertrophy and atrophy (Latres et al., 2005). However, unique mechanisms are induced during skeletal muscle atrophy, which have been shown to mediate a large part of the phenotypic

Akt inhibition of FOXO transcription factors blocks upregulation of MuRF1 and MAFbx

Studies of differentiated myotube cultures demonstrated that treatment of myotubes with the cachectic glucocorticoid dexamethasone promotes enhanced protein breakdown and increased expression of genes broadly involved in the ubiquitin-proteasome proteolytic pathway (Du, Mitch, Wang, & Price, 2000; Hong & Forsberg, 1995; Wang, Luo, Wang, & Hasselgren, 1998). More recent studies showed that in vitro treatment of myotubes with dexamethasone induces atrophy, accompanied by the specific increased

mTOR blocks upregulation of MuRF1 and MAFbx

A second, FOXO-independent, anti-atrophy checkpoint downstream of Akt activation was recently demonstrated, by isolating a set of genes regulated by dexamethasone and inversely regulated by IGF-1 (Latres et al., 2004). The genes, which were regulated by IGF-1 in skeletal muscle could be blocked by inhibitors of PI3K, consistent with the previous work demonstrating a requisite role for the PI3K/Akt/FOXO pathway. However, it was shown that inhibition downstream of Akt, at the level of mTOR, could

Triggers of atrophy: the NF-κB pathway and p38

Several cytokines have been shown to induce muscle wasting, most notably TNFα, a pro-inflammatory secreted cytokine that was originally called “cachectin” (Argiles & Lopez-Soriano, 1999; Beutler, Mahoney, Le Trang, Pekala, & Cerami, 1985; Tisdale, 1997). TNFα levels are elevated in the circulations of patients with cancer cachexia, contributing to negative nitrogen balance (Argiles & Lopez-Soriano, 1999). TNFα binding to its receptor induces the activation of the Rel/NF-κB (NF-κB) family of

Conclusion

A considerable amount of recent progress has been made in the understanding of the signaling pathways which mediate skeletal muscle hypertrophy and atrophy. Whereas it was appreciated many years ago that hypertrophy comes about via an increase in the rate of protein synthesis, and atrophy through an increase in protein degradation, only now can specific signaling pathways be drawn, since molecular mediators of hypertrophy and atrophy in skeletal muscle have only recently begun to be determined.

Acknowledgements

Thanks to Dr. G.D. Yancopoulos, Dr. P.R.Vagelos, Dr. L.S. Schleifer as well as the rest of the Regeneron Community, for their enthusiastic support and input. Thank you for Trevor Stitt for comments on this manuscript. Sincere apologies to scientific colleagues whose work was omitted from this review due to space constraints.

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