Skeletal muscle hypertrophy and regeneration: interplay between the myogenic regulatory factors (MRFs) and insulin-like growth factors (IGFs) pathways

Abstract

Adult skeletal muscle can regenerate in response to muscle damage. This ability is conferred by the presence of myogenic stem cells called satellite cells. In response to stimuli such as injury or exercise, these cells become activated and express myogenic regulatory factors (MRFs), i.e., transcription factors of the myogenic lineage including Myf5, MyoD, myogenin, and Mrf4 to proliferate and differentiate into myofibers. The MRF family of proteins controls the transcription of important muscle-specific proteins such as myosin heavy chain and muscle creatine kinase. Different growth factors are secreted during muscle repair among which insulin-like growth factors (IGFs) are the only ones that promote both muscle cell proliferation and differentiation and that play a key role in muscle regeneration and hypertrophy. Different isoforms of IGFs are expressed during muscle repair: IGF-IEa, IGF-IEb, or IGF-IEc (also known as mechano growth factor, MGF) and IGF-II. MGF is expressed first and is observed in satellite cells and in proliferating myoblasts whereas IGF-Ia and IGF-II expression occurs at the state of muscle fiber formation. Interestingly, several studies report the induction of MRFs in response to IGFs stimulation. Inversely, IGFs expression may also be regulated by MRFs. Various mechanisms are proposed to support these interactions. In this review, we describe the general process of muscle hypertrophy and regeneration and decipher the interactions between the two groups of factors involved in the process.

Fig. 1

The myogenic regulatory factors pathway during skeletal muscle regeneration. Satellite cells are normally quiescent expressing Pax 7 involved in their survival. Upon muscle damage, they become activated and express Myf5 to proliferate as myoblast, then expressing MyoD. MyoD constitutes the key MRF, which regulates myoblast differentiation during muscle regeneration. Indeed, the MyoD-positive cells exit from the cell cycle and express myogenin to initiate the differentiation and fusion into myotube. These myotubes present central nuclei. The expression of Mrf4 allows maturation of myotube in myofiber that present peripheric nuclei

Fig. 2

Models of IGF-induced muscle cell proliferation and differentiation. The binding of IGF-I to its receptor activates two main pathways: the MAPK pathway that allows myoblast proliferation through the activation of ERK and cyclin, and the PI3K/Akt pathway that promotes muscle cell differentiation and hypertrophy through activation of muscle protein synthesis and inhibition of muscle proteolysis. IGF-II also mediates the effects of IGF-I by its binding to the IGF-IR. These signaling pathways are detailed in the text

Fig. 3

Interplay between the MRFs and IGFs pathways during myogenesis and muscle regeneration. The IGF pathway regulates MRFs expression and activity. Indeed, the activity of MyoD, the key regulator of muscle regeneration, is enhanced by the activation of the PI3K/Akt pathway in two ways: (i) interaction of active Akt with PHB2 that releases MyoD from the inhibitory effects of PHB2 (known to complex MyoD and Mef2, inhibiting their activity), (ii) inhibition of MyoD proteolysis by active mTOR, the downstream target of Akt. Active MyoD then induces the transcription of myogenin (to allow myoblast differentiation) or other muscle-specific genes and remove the inhibition of HDAC on the transcription of follistatin, which inhibits the negative regulator of myogenesis, myostatin. MRFs may also modulate the IGF pathway through different ways: (i) induction of the transcription of IGF-II (known to be involved in myoblast differentiation), (ii) inhibition of Foxo 3a that induces muscle proteolysis and PTEN known to inhibit PI3K, both regulations mediated by miR 486, (iii) slowdown in myogenesis through regulation of the expression of IGF-II by SKIP or induction of miR 133 to block IGF-R, each way constituting a negative feedback of MRFs on IGF expression and myogenesis