Metabolic-Sensing of the Skeletal Muscle Clock Coordinates Fuel Oxidation

Authors

Hongshan Yin
Weini Li
Somik Chatterjee
Xuekai Xiong
Pradip Saha
Vijay Yechoor
Ke Ma

Publication Date

5-1-2020

Journal

The FASEB Journal

DOI

10.1096/fj.201903226RR

PMID

32212194

PMCID

PMC7597556

PubMedCentral® Posted Date

5-1-2021

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

ARNTL Transcription Factors, Animals, Circadian Clocks, Fatty Acids, Gene Expression Regulation, Glucose, Homeostasis, Liver, Mice, Mice, Transgenic, Muscle, Skeletal, circadian clock, skeletal muscle, glucose metabolism, fatty acid metabolism, hepatic steatosis

Abstract

Circadian 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 metabolic-sensing function of skeletal muscle clock in partitioning nutrient flux between muscle and liver to maintain whole-body lipid and glucose homeostasis.

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