FoxO1: a novel insight into its molecular mechanisms in the regulation of skeletal muscle differentiation and fiber type specification

Abstract

FoxO1, a member of the forkhead transcription factor forkhead box protein O (FoxO) family, is predominantly expressed in most muscle types. FoxO1 is a key regulator of muscle growth, metabolism, cell proliferation and differentiation. In the past two decades, many researches have indicated that FoxO1 is a negative regulator of skeletal muscle differentiation while contrasting opinions consider that FoxO1 is crucial for myoblast fusion. FoxO1 is expressed much higher in fast twitch fiber enriched muscles than in slow muscles and is also closely related to muscle fiber type specification. In this review, we summarize the molecular mechanisms of FoxO1 in the regulation of skeletal muscle differentiation and fiber type specification.

Keywords: FoxO1; differentiation; fiber type specification; molecular mechanisms; skeletal muscle.

Figure 1. FoxO1 signaling pathway involved in skeletal muscle differentiation

The FoxO1 upstream signals including IGFs, insulin and IRS regulate FoxO1 transcriptional activity through phosphorylating FoxO1 in a PI3K-Akt dependent manner. Phosphorylated FoxO1 will be excluded from nucleus and thus loses its capacity of binding to target regulatory elements. In addition, other signals, such as cGKI and Rho/ROCK signaling, directly mediate FoxO1 transcriptional activity by phosphorylation. Myostatin, MEF2C, MyoD and mTOR are downstream factors of FoxO1. FoxO1 negatively regulates myoblast early differentiation through promoting myostatin and inhibiting MEF2C, MyoD and mTOR. Then the decrease of MEF2C, MyoD and mTOR delays myoblast early differentiation. In addition, the relationship among FoxO1, mTOR, IGF-II and PI3K/Akt pathway presents a feedback loop that can preferably fine-tune the regulation of muscle differentiation. Moreover, FoxO1 can inhibit early step of myoblast differentiation through interacting with Notch signaling and promoting corepressor clearance and recruiting the coactivator of Csl, leading activation of Hes family, which is considered to be a myoblast differentiation repressor. Notably, although FoxO1 suppresses the early muscle differentiation process, FoxO1 is required for myoblast terminal differentiation fusion into myotubes. However, the molecular mechanism in which FoxO1 is required for myotube fusion has remained poorly understood.

Figure 2. Mechanisms of FoxO1 in the regulation of slow skeletal muscle fiber gene expression

FoxO1 downregulates calcineurin (CaN), CaMK and MEF2C expression, leading to a decrease of MEF2C that can increase the transcriptional activation of slow fiber genes, to inhibit slow fiber genes expression. In addition, PGC1α induces fiber-type switching from glycolytic toward oxidative fibers. FoxO1 may interact with PGC1α to inhibit certain functions of PGC1α, inhibiting expression of slow fiber gene.