Myostatin and the skeletal muscle atrophy and hypertrophy signaling pathways

Abstract

Myostatin, a member of the transforming growth factor-β superfamily, is a potent negative regulator of skeletal muscle growth and is conserved in many species, from rodents to humans. Myostatin inactivation can induce skeletal muscle hypertrophy, while its overexpression or systemic administration causes muscle atrophy. As it represents a potential target for stimulating muscle growth and/or preventing muscle wasting, myostatin regulation and functions in the control of muscle mass have been extensively studied. A wealth of data strongly suggests that alterations in skeletal muscle mass are associated with dysregulation in myostatin expression. Moreover, myostatin plays a central role in integrating/mediating anabolic and catabolic responses. Myostatin negatively regulates the activity of the Akt pathway, which promotes protein synthesis, and increases the activity of the ubiquitin-proteasome system to induce atrophy. Several new studies have brought new information on how myostatin may affect both ribosomal biogenesis and translation efficiency of specific mRNA subclasses. In addition, although myostatin has been identified as a modulator of the major catabolic pathways, including the ubiquitin-proteasome and the autophagy-lysosome systems, the underlying mechanisms are only partially understood. The goal of this review is to highlight outstanding questions about myostatin-mediated regulation of the anabolic and catabolic signaling pathways in skeletal muscle. Particular emphasis has been placed on (1) the cross-regulation between myostatin, the growth-promoting pathways and the proteolytic systems; (2) how myostatin inhibition leads to muscle hypertrophy; and (3) the regulation of translation by myostatin.

Fig. 1

Schematic illustration of myostatin control of skeletal muscle development and post-natal growth. Differentiation of skeletal muscle cells sequentially requires growth arrest followed by the onset of a timely expression of muscle-specific genes. Cell cycle withdrawal and each phase of differentiation are coordinated by activation of specific cyclins, cyclin-dependent kinases (CDK), CDK inhibitors (CDKI), and muscle regulatory factors (MRFs) that lead to the induction of specific muscle proteins, such as myosin heavy chains (MHC). Upper panel During the proliferation phase, myostatin can up-regulate p21 (a CDKI) and, as a consequence, the levels of CDK2 and CDK4 and phosphorylated RB decrease, leading to cell cycle arrest. Myostatin further inhibits differentiation by down-regulating MRFs (such as MyoD and myogenin) and the transcription factor PAX3. RAPTOR blockade also facilitates myostatin inhibition of muscle differentiation. Lower panel Myostatin also contributes to the inhibition of satellite cell activation and self-renewal in mature muscle cells by down-regulating the transcription factor PAX7

Fig. 2

Schematic illustration of myostatin roles in protein synthesis and degradation. First, the myostatin–SMAD pathway alters the activity of the protein kinase AKT, thereby inhibiting the assembly of the translation initiation complex and protein synthesis. AKT blocks FOXO nuclear translocation to inhibit the expression of MAFbx and MuRF1 and consequently protein degradation. Second, myostatin also suppresses the AKT pathway and signals through FOXO transcription factors to increase protein breakdown via the activity of the ubiquitin–proteasome system. Finally myostatin could inhibit also the autophagy–lysosome system