FoxO1 inhibits skeletal muscle hypertrophy through mTOR-independent mechanisms

The canonical Akt/mTOR signaling pathway plays a strong role in promoting skeletal muscle hypertrophy through regulating anabolic and catabolic signaling cascades. The transcription factor, FoxO1, a downstream molecular target of Akt signaling, may play a negative role in skeletal muscle hypertrophy through suppression of growth signaling and/or upregulation of atrophy gene expression. Using a transgenic mouse model in which FoxO1 is specifically expressed within skeletal muscle, we tested the hypotheses: (a) that FoxO1 inhibits skeletal muscle hypertrophy in vivo; and (b) that inhibition of skeletal muscle hypertrophy conferred through FoxO1 expression is associated with suppression of Akt/mTOR signaling and upregulation of muscle atrophy F-box (MAFbx/atrogin-1) gene expression. The findings confirm that FoxO1 inhibits skeletal muscle hypertrophy associated with 2 wks of mechanical overload (synergist ablation), evidenced through dampened increases in muscle mass, protein content, and muscle cross sectional area. We conclude that FoxO1 overexpression hampers the ability of skeletal muscle to hypertrophy, and that this suppression involves mechanisms independent of mTOR signaling.