Protective effects of Mkl1/2 against lipodystrophy and muscle atrophy via PI3K/AKT-independent FoxO repression

Abstract

ABSTRACTFoxO transcription factors are involved in the pathogenesis of lipodystrophy and muscle atrophy. FoxO proteins are phosphorylated and inactivated by PI3K/AKT signaling; however, little is known about FoxO repressors other than this pathway. Our study showed that the Srf cofactors Mkl1 and Mkl2 directly repressed FoxO transcriptional activity, independent of the PI3K/AKT pathway. Loss ofMkl1/2led to the overactivation of FoxO, which impaired the maintenance of both white adipose tissue (WAT) and skeletal muscle. InMkl2-deficient preadipocytes,Pparγwas suppressed and white adipogenesis was severely impaired. In myotubes, Mkl1 and Mkl2 suppressed the expression of atrophy-related genes (atrogenes) induced by FoxO.Mkl1expression was reduced at the onset of muscle atrophyin vivo, and exogenous supplementation of skeletal muscle Mkl1 suppressed atrogene expression and induced muscle hypertrophy. Finally, both Mkl2 nuclear localization andMkl1/2expression were upregulated by exercise, suggesting thatMkl1/2is involved in the inhibitory effect of exercise on muscle atrophy. These findings indicate that Mkl1/2 act as PI3K/AKT signaling-independent repressors of FoxO and are essential for adipose and muscle tissue homeostasis.