Circadian Clock Regulation of HIF1a-dependent Skeletal Muscle Metabolism during Diet-induced Obesity

Project Summary The mammalian circadian clock is comprised of an autoregulatory transcription-translation feedback loop expressed in the brain and peripheral tissues that coordinates metabolism with the sleep-wake cycle. Epidemiological and genetic studies have shown that disruption of circadian rhythms leads to accelerated and worsened symptoms of metabolic syndrome. Evidence from skeletal muscle clock mutants in lean mice indicates that loss of clock activators leads to impaired glucose tolerance and reduced insulin-stimulated glucose uptake. Additionally, our lab has shown that genetic abrogation of the skeletal muscle molecular clock in vitro leads to skeletal muscle dysfunction due to reduced mitochondrial oxidative respiration and impaired activation of the hypoxia-inducible factor (HIF) pathway. My preliminary data demonstrate that during the nutrient stress condition of diet-induced obesity (DIO), HIF1α pathway target gene expression is elevated in skeletal muscle and loss of clock activator, BMAL1, leads to reduced HIF1α pathway target gene expression and impaired glucose tolerance in mice. Additionally, the clock-disrupted mice have reduced muscle mass which may be a preliminary sign of sarcopenia. We generated clock-disrupted HIF1α stabilized mice to determine whether this could rescue the muscle phenotypes seen in the clock-disrupted mice. Glucose tolerance and HIF1α target gene expression were rescued in the HIF1α stabilized mice. These data suggest that the skeletal muscle molecular clock regulates glucose metabolism through the HIF pathway, however, the specific mechanisms of this regulatory interaction and the role of HIF1α in maintaining muscle mass remain unknown. The scientific premise of the present proposal is that the skeletal muscle molecular clock controls whole-body glucose metabolism and skeletal muscle metabolism during DIO through regulation of HIF pathway transcription. The studies in this proposal will provide greater insight into clock control of skeletal muscle metabolism during nutrient stress and elucidate the mechanism of interaction between the skeletal muscle molecular clock and HIF pathways.