Skeletal Muscle Clock Is Essential for Nutrient-Sensing and Interorgan Metabolic Fuel Partitioning

Abstract

The circadian clock exerts temporal control in metabolism and its disruption leads to the development of diabetes and obesity. Tissue-intrinsic clock circuits are integral components of global metabolic homeostasis, although how they sense nutrient signals to orchestrate metabolic flux is not clear. Skeletal muscle is major site for metabolic substrate oxidation, and its utilization of glucose and fatty acid depends on availability of nutrients accompanying feeding-fasting transitions. Interestingly, nearly 30% of rhythmic transcripts in skeletal muscle belongs to metabolism. By generating a mouse model with myocyte-selective ablation of the clock transcription activator Bmal1, here we show that cell-autonomous muscle clock plays an essential role in coordinating nutrient utilization with feeding-fasting induced cycles. Bmal1 in skeletal muscle was robustly induced by feeding, and its loss markedly impaired feeding-induced switch to glucose metabolism from fatty acid utilization. As a result, Bmal1-deficient muscle displays nearly 50% reduction of glucose oxidation whereas fatty acid oxidation was enhanced, resembling a constant fasting state. This metabolic shift was accompanied by muscle fiber type switching to an oxidative phenotype, and led to a remarkable resistance to hepatic lipid accumulation induced by prolonged fasting or high-fat diet feeding. In contrast, systemic fasting glucose levels in muscle Bmal1-deficient mice was elevated, which is due to a failure of suppressing hepatic glucose output as revealed by hyperinsulinemic-euglycemic glucose clamp study. Collectively, our results reveal a novel function of the Bmal1-driven muscle clock as a key metabolic sensor that coordinates metabolic fuel oxidation with oscillatory nutrient availability in fasting-feeding cycles. This temporal mechanism in orchestrating global nutrient flux may contribute to metabolic abnormalities induced by circadian misalignment. Disclosure K. Ma: None. S. Chatterjee: None. H. Yin: None.