Cancer-induced FOXP1 disrupts and reprograms skeletal-muscle circadian transcription in cachexia

Cancer cachexia is a debilitating metabolic disorder characterized by involuntary loss of body and muscle mass, leading to increased morbidity and mortality. We previously found that forkhead box P1 (FoxP1) upregulation in skeletal muscle causes muscle wasting and is required for muscle wasting in response to cancer. However, transcriptional networks targeted by FoxP1 in skeletal muscles undergoing cancer-induced wasting remain largely unknown. Here, we identify FoxP1 as a key disruptor of the skeletal-muscle clock in response to cancer that reprograms circadian patterns of gene expression at cachexia onset. Specifically, we show that cancer-induced FoxP1 rewires the skeletal-muscle circadian transcriptome toward pathways associated with muscle wasting and disrupts the temporal patterning of pathways governing glucose, lipid, and oxidative metabolism. These findings thus implicate cancer/disease-specific functions of FOXP1 in the disruption and reprograming of the skeletal-muscle circadian transcriptome, which may contribute to muscle wasting and the development of cachexia.