Mammalian target of rapamycin (mTOR) signaling network in skeletal myogenesis

Abstract

Mammalian (or mechanistic) target of rapamycin (mTOR) regulates a wide range of cellular and developmental processes by coordinating signaling responses to mitogens, nutrients, and various stresses. Over the last decade, mTOR has emerged as a master regulator of skeletal myogenesis, controlling multiple stages of the myofiber formation process. In this minireview, we present an emerging view of the signaling network underlying mTOR regulation of myogenesis, which contrasts with the well established mechanisms in the regulation of cell and muscle growth. Current questions for future studies are also highlighted.

FIGURE 1.

Rapamycin-sensitive mTOR signaling controls distinct stages of skeletal myogenesis. Formation of nascent myotubes in vitro and myofibers in vivo is regulated by mTOR in a kinase-independent manner, whereas maturation of myotubes/myofibers requires mTOR kinase activity.

FIGURE 2.

Two rapamycin-sensitive myogenic mTOR signaling pathways. A kinase-independent mTOR pathway controls IGF2 expression through transcriptional regulation at a muscle-specific enhancer, as well as through suppression of miR-125b, which targets Igf2. IGF2 regulates myogenesis by activating the IGF1 receptor (IGF-IR) and PI3K/Akt signaling. A kinase-dependent mTOR pathway regulates myocyte fusion and myotube/myofiber maturation by controlling follistatin expression via a MyoD/miR-1/HDAC4 pathway. Amino acid signals are most likely upstream of the IGF2 pathway, but their role in the follistatin pathway is not clear.

FIGURE 3.

mTORC1 and mTORC2 in myogenic regulation. mTORC1 has a negative role in myogenic differentiation through phosphorylation and suppression of IRS1 or mTORC2. The positive function of mTORC2 may be mediated by two substrates of the kinase, PKCα and Akt. IGF-IR, IGF1 receptor.