Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion

Nat Med. 2017 Feb;23(2):223-234. doi: 10.1038/nm.4245. Epub 2016 Dec 19.


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.

MeSH terms

  • AMP Deaminase / metabolism
  • Amino Acids, Branched-Chain / metabolism
  • Animals
  • Blotting, Western
  • Body Composition
  • Circadian Rhythm / genetics
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Energy Metabolism
  • Epigenesis, Genetic
  • Gene Knockdown Techniques
  • Glucose Clamp Technique
  • Histone Code / genetics
  • Histone Deacetylases / genetics*
  • Insulin Resistance / genetics*
  • Lipid Metabolism / genetics*
  • Mice
  • Muscle Fatigue / genetics*
  • Muscle Strength / genetics*
  • Muscle, Skeletal / metabolism*
  • Physical Conditioning, Animal*
  • Physical Endurance / genetics*
  • Proteomics
  • Real-Time Polymerase Chain Reaction


  • Amino Acids, Branched-Chain
  • Histone Deacetylases
  • histone deacetylase 3
  • AMP Deaminase
  • AMPD3 protein, mouse