Type 2 diabetes and insulin resistance are associated with reduced glucose utilization in the muscle and poor exercise performance. Here we find that depletion of the epigenome modifier histone deacetylase 3 (HDAC3) specifically in skeletal muscle causes severe systemic insulin resistance in mice but markedly enhances endurance and resistance to muscle fatigue, despite reducing muscle force. This seemingly paradoxical phenotype is due to lower glucose utilization and greater lipid oxidation in HDAC3-depleted muscles, a fuel switch caused by the activation of anaplerotic reactions driven by AMP deaminase 3 (Ampd3) and catabolism of branched-chain amino acids. These findings highlight the pivotal role of amino acid catabolism in muscle fatigue and type 2 diabetes pathogenesis. Further, as genome occupancy of HDAC3 in skeletal muscle is controlled by the circadian clock, these results delineate an epigenomic regulatory mechanism through which the circadian clock governs skeletal muscle bioenergetics. These findings suggest that physical exercise at certain times of the day or pharmacological targeting of HDAC3 could potentially be harnessed to alter systemic fuel metabolism and exercise performance.
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We thank S. Burden (New York University) for MLC-Cre mice, J. Hogenesch (University of Pennsylvania) for processed data from circaDB, M. Birnbaum and J. Baur (University of Pennsylvania) for helpful discussion, S. Guo (Texas A&M University) for help with the EPS procedure, P. Zhang (Baylor College of Medicine) for adenoviral plasmids, S. Hui and J. Park (Princeton University) for analysis of metabolomics data, V. Narkar (University of Texas Health Science Center) for the immunostaining protocol, M. Goncalves and C. Lanzillotta (University of Pennsylvania) for technical assistance. We thank the Penn Diabetes Center (DK19525) Functional Genomics Core for nucleotide sequencing, the Mouse Metabolic Phenotyping Core for clamp experiments, the Penn Muscle Institute Muscle Physiology Assessment Core for muscle contraction study, and the Princeton/Penn Regional Metabolomics Core for flux and lipid analysis. We thank the Baylor Diabetes Center (DK079638) Metabolism Core for Seahorse analysis and Vanderbilt MMPC (DK59637) for lipidomics analysis. The Rockefeller Proteomics Resource Center is supported by the Leona M. and Harry B. Helmsley Charitable Trust. This work was supported by NIH grants CA211437 (W.L.), DK043806 (M.A.L.) and DK099443 (Z.S.).
The authors declare no competing financial interests.
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Hong, S., Zhou, W., Fang, B. et al. Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. Nat Med 23, 223–234 (2017). https://doi.org/10.1038/nm.4245