FoxO6 and PGC-1α form a regulatory loop in myogenic cells

Transcription factors of the FoxO (forkhead box O) family regulate a wide range of cellular physiological processes, including metabolic adaptation and myogenic differentiation. The transcriptional activity of most FoxO members is inhibitory to myogenic differentiation and overexpression of FoxO1 inhibits the development of oxidative type I fibres in vivo. In this study, we found that FoxO6, the last discovered FoxO family member, is expressed ubiquitously in various tissues but with higher expression levels in oxidative tissues, such as brain and oxidative muscles. Both the expression level and promoter activity of FoxO6 were found to be enhanced by PGC-1 alpha (peroxisome-proliferator-activated receptor gamma co-activator 1 alpha), thus explained its enriched expression in oxidative tissues. We further demonstrated that FoxO6 represses the expression of PGC-1 alpha via direct binding to an upstream A/T-rich element (AAGATATCAAAACA,-2228-2215) in the PGC-1 alpha promoter. Oxidative low-intensity exercise induced PGC-1 alpha but reduced FoxO6 expression levels in hind leg muscles, and the binding of FoxO6 to PGC-1 alpha promoter was also prevented by exercise. As FoxO6 promoter can be co-activated by PGC-1 alpha and its promoter in turn can be repressed by FoxO6, it suggests that FoxO6 and PGC-1 alpha form a regulatory loop for setting oxidative metabolism level in the skeletal muscle, which can be entrained by exercise.