Metabolic‐sensing of the skeletal muscle clock coordinates fuel oxidation

Abstract

Abbreviations: Bmal1, brain and muscle Arnt-like protein 1; CLOCK, circadian locomotor output cycles kaput; MyHC, myosin heavy chain; ROR, RAR-related orphan receptor. AbstractCircadian clock confers temporal control in metabolism, with its disruption leading to the development of insulin resistance. Metabolic substrate utilization in skeletal muscle is coordinated with diurnal nutrient cycles. However, whether the molecular clock is involved in this coordination is largely unknown. Using a myocyte-selective genetic ablation mouse model of the essential clock activator Bmal1, here we identify muscle-intrinsic clock as a sensor of feeding cues to orchestrate skeletal muscle oxidation required for global nutrient flux. Bmal1 in skeletal muscle responds robustly to feeding in vivo and insulin induces its expression. Muscle Bmal1 deficiency impaired the transcriptional control of glucose metabolic pathway, resulting in markedly attenuated glucose utilization and fasting hyperglycemia. Notably, the loss of Bmal1 response to feeding abolished fasting-to-feeding metabolic fuel switch from fatty acids to glucose in skeletal muscle, leading to the activation of energy-sensing pathways for fatty acid oxidation. These altered metabolic substrate oxidations in Bmal1-deficient muscle ultimately depleted circulating lipid levels that prevented hepatic steatosis. Collectively, our findings highlight the key role of the metabolicsensing function of skeletal muscle clock in partitioning nutrient flux between muscle and liver to maintain whole-body lipid and glucose homeostasis. K E Y W O R D Scircadian clock, skeletal muscle, glucose metabolism, fatty acid metabolism, hepatic steatosis

Rap1 in the VMH regulates glucose homeostasis

“…Hyperinsulinemic-euglycemic clamp studies were performed at the Mouse Metabolism and Phenotyping Core at Baylor College of Medicine as described previously ( 63 , 64 ). Mice were anesthetized, and a midline neck incision was made to expose the jugular vein.…”

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“…Harfmann et al demonstrated that post developmental loss of Bmal1, a regulator of circadian rhythm, in skeletal muscle leads to decreased fat mass, impaired glucose uptake, and insulin resistance [111]. Similar results are seen by others where a loss of muscle Bmal1 leads to the upregulation of lipid metabolism and down-regulation of glucose oxidation [112][113][114]. Additionally, loss of other clock components leads to decreased skeletal muscle mass and function [115].…”

Photoperiod Manipulation Reveals a Light-Driven Component to Daily Patterns of Ventilation in Male C57Bl/6J Mice

“…Therefore, shortened photoperiods may promote a switch toward an OSA phenotype, and potentially explain why OSA symptoms are more severe in the winter (Cassol et al, 2012). One explanation for the decrease in RER under L5 may be that altering photoperiod drives changes in peripheral expression patterns of clock genes, which can have direct effects on glucose and lipid metabolism (Sosniyenko et al, 2010; Sen et al, 2018; Yin et al, 2020). However, further studies are needed to understand the contributions of photoperiodic changes in clock gene expression to metabolic and ventilatory patterns.…”