In adult organisms, skeletal muscles constantly adjust the rate of protein synthesis and undergo myonuclear turnover, via regenerative events, in response to pathways elicited by local and systemic cues.
The IGF1 signaling is the prototypical pathway that promotes myofiber hypertrophy by stimulating both protein synthesis and muscle regeneration [3
]. Local increase in IGF1 is stimulated following muscle exercise [5
], whereas systemic IGF1 is released in response to endocrine changes and mediates the effect of anabolic hormones [6
]. Furthermore, the IGF1 pathway is activated by nutrients and insulin. Upon IGF1 binding to its membrane receptor (IGFR), the phosphorylation of the insulin receptor substrate 1 (IRS-1) and the engagement of the PI3K-Akt signaling stimulate a number of distinct downstream events [7
]. Activation of mTOR [9
] results in an increase in protein translation via the activation of the positive regulator of protein translation p70S6K, and the inhibition of PHAS-1, a negative regulator of translation [10
]. Simultaneous inhibition of glycogen synthase kinase 3 beta (GSK3β) and forkhead box, subgroup O (FOXO) transcription factors by Akt-mediated phosphorylation also promotes hypertrophy by preventing the activation of atrophic or catabolic signals [12
]. Furthermore, conflicting data exist regarding the contribution of calcineurin – a serine/threonine protein phosphatase that activates nuclear factor of activated T cells (NFAT) transcription factors by dephosphorylation [15
] – in IGF1-mediated hypertrophy [16
The ability of the IGF1 pathway to stimulate proliferation of muscle progenitors (e.g. satellite cells) appears to rely on the parallel activation of the Ras-Raf-MEK-ERK pathway, which promotes proliferation and survival [18
]. Furthermore, a unique property of the IGF1 pathway resides in its ability to promote both proliferation and differentiation. We have recently reported on the mechanism by which IGF1-activated Akt1 and 2 stimulate the recruitment of the acetyltransferases p300 and PCAF to the chromatin of muscle loci, an event necessary to initiate the transcription of muscle specific genes in response to regeneration cues [21•
Myostatin is a member of the TGFβ family of signal transduction proteins that negatively regulates muscle mass in the adults by inhibiting muscle regeneration [22
]. Indeed, the increase in muscle mass observed in myostatin-null animals predominantly results from an increase in the number of muscle fibers (hyperplasia). Myostatin has been isolated as the gene mutated in cattle characterized by abnormal hypertrophy of the skeletal muscle [24
]. Similarly, myostatin-null mice display an increase in muscle mass relative to control animals [22
], and gene mutation that precludes myostatin expression has been identified in humans and dogs showing a hyper-muscular phenotype [25
]. Myostatin effect on muscles is opposed by other members of the TGFβ family such as follistatin and follistatin-related gene [27
]. Consistently, systemic overexpression of myostatin in mice causes significant loss in muscle mass, and the effect is reversed by follistatin administration [28
]. Thus, factors that interfere with myostatin activity can be considered anabolic signals.
Other important regulators of muscle regeneration are the Notch signaling, which negatively control the fate of muscle stem cells, their recruitment and fusion into myofibers [29
] and IL4, which is induced in myotubes in response to the calcineurin–NFAT signaling and stimulates myoblast fusion into preexisting myotubes [31
Steroid hormones, and in particular, androgens, are potent anabolic factors which exert their effect by directly regulating gene transcription [32
]. However, it is unclear if their anabolic activity relies more on increased protein synthesis or an enhanced regeneration-mediated myonuclear turnover.