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

Sungguan Hong, Wenjun Zhou, Bin Fang, Wenyun Lu, Emanuele Loro, Manashree Damle, Guolian Ding, Jennifer Jager, Sisi Zhang, Yuxiang Zhang, Dan Feng, Qingwei Chu, Brian D. Dill, Henrik Molina, Tejvir S. Khurana, Joshua D. Rabinowitz, Mitchell A. Lazar, Zheng Sun

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)223-234
Number of pages12
JournalNature Medicine
Volume23
Issue number2
DOIs
StatePublished - Feb 1 2017

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion'. Together they form a unique fingerprint.

  • Cite this

    Hong, S., Zhou, W., Fang, B., Lu, W., Loro, E., Damle, M., Ding, G., Jager, J., Zhang, S., Zhang, Y., Feng, D., Chu, Q., Dill, B. D., Molina, H., Khurana, T. S., Rabinowitz, J. D., Lazar, M. A., & Sun, Z. (2017). Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. Nature Medicine, 23(2), 223-234. https://doi.org/10.1038/nm.4245