FOXO1 suppresses PGC-1β gene expression in skeletal muscles.

Peroxisome proliferator-activated receptor-gamma coactivator-1 beta (PGC-1 beta) is a transcriptional regulator whose increased expression activates energy expenditure-related genes in skeletal muscles. However, how PGC-1 beta is regulated remains largely unclear. Here, we show that PGC-1 beta gene expression is negatively correlated with the expression of a transcription factor, forkhead box protein O1 (FOXO1), whose expression is increased during muscle atrophy. In the skeletal muscles of FOXO1-overexpressing transgenic mice, PGC-1 beta gene expression is decreased. Denervation or plaster cast-based unloading, as well as fasting, increases endogenous FOXO1 expression in skeletal muscles, with decreased PGC-1 beta expression. In the skeletal muscles of FOXO1-knockout mice, the decrease in PGC-1 beta expression caused by fasting was attenuated. Tamoxifen-inducible FOXO1 activation in C2C12 myoblasts causes a marked decrease of PGC-1 beta expression. These findings together reveal that FOXO1 activation suppresses PGC-1 beta expression. During atrophy with FOXO1 activation, decreased PGC-1 beta may decrease energy expenditure and avoid wasting energy.