From Nutrient to MicroRNA: a Novel Insight into Cell Signaling Involved in Skeletal Muscle Development and Disease

Abstract

Skeletal muscle is a remarkably complicated organ comprising many different cell types, and it plays an important role in lifelong metabolic health. Nutrients, as an external regulator, potently regulate skeletal muscle development through various internal regulatory factors, such as mammalian target of rapamycin (mTOR) and microRNAs (miRNAs). As a nutrient sensor, mTOR, integrates nutrient availability to regulate myogenesis and directly or indirectly influences microRNA expression. MiRNAs, a class of small non-coding RNAs mediating gene silencing, are implicated in myogenesis and muscle-related diseases. Meanwhile, growing evidence has emerged supporting the notion that the expression of myogenic miRNAs could be regulated by nutrients in an epigenetic mechanism. Therefore, this review presents a novel insight into the cell signaling network underlying nutrient-mTOR-miRNA pathway regulation of skeletal myogenesis and summarizes the epigenetic modifications in myogenic differentiation, which will provide valuable information for potential therapeutic intervention.

Keywords: disease; mTOR; microRNA; nutrient; signaling pathways; skeletal myogenesis.

Figure 1

mTOR signaling in skeletal myogenesis. PLD activates kinase-independent mTOR and subsequently modulates myogenic transcription of IGF-II. The Rag GTPases and Rheb activate mTORC1, which subsequently inhibit PI3K-Akt signaling by IRS1 phosphorylation. PLD1 also activates mTORC2 and potentially regulates the phosphorylation of Akt and PKCα. The phosphorylation of S6K1 can repress myogenic function of mTORC2.

Figure 2

A model for nutrients-mTOR-miRNA signaling in skeletal myogenesis. MiRNA biogenesis in response to nutrient conditions regulates skeletal myogenesis via an mTORC1-MDM2-Drosha signaling. Meanwhile, mTOR controls skeletal myogenesis through miR-17-92/ENH1/Id1 regulatory axis. Besides, nutrient regulation of certain miRNA expression during skeletal myogenesis depends on two rapamycin-sensitive myogenic mTOR signaling pathways. A kinase-dependent mTOR pathway regulates myogenesis by governing the expressions of various miRNAs (miR-1, miR-133 and miR-206) through stabilizing major myogenic transcription factor MyoD. A kinase-independent mTOR signaling governs IGF-II transcription at a muscle-specific enhancer via its negative regulation of miR-125b level, and IGF-II in turn regulates skeletal myogenesis through activating the IGF-I receptor (IGF-IR) and PI3K/Akt signaling.