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

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.

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Figure 1: Deletion of HDAC3 in skeletal muscle reduces glucose uptake and insulin sensitivity independently of the upstream insulin signaling.
Figure 2: HDAC3 deletion reduces glucose utilization during muscle contractions but enhances exercise endurance and oxidative metabolism.
Figure 3: HDAC3 regulates muscle fuel preference and controls amino acid metabolism.
Figure 4: Enhanced amino acid catabolism underlies the glucose-to-lipid fuel switch in HDAC3-depleted muscles.
Figure 5: Nonbiased identification of the circadian clock as an upstream regulator of muscle HDAC3.
Figure 6: HDAC3 couples circadian cues with the regulation of genes in anaplerotic reactions and amino acid catabolism.

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Acknowledgements

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.).

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Z.S. and M.A.L. conceived the study and designed experiments. S.H., W.Z., W.L., E.L., G.D., J.J., S.Z., Y.Z., D.F., Q.C., B.D.D. and Z.S. conducted experiments. S.H., W.Z., B.F., W.L., M.D., G.D., S.Z., B.D.D., H.M. and Z.S. analyzed the data. E.L., T.S.K., J.D.R., M.A.L. and Z.S. interpreted the data. M.A.L. and Z.S. acquired funding. Z.S. wrote the manuscript with input from other authors.

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Correspondence to Mitchell A Lazar or Zheng Sun.

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The authors declare no competing financial interests.

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Supplementary Figures

Supplementary Figures 1–7 (PDF 2216 kb)

Supplementary Table 1

Raw data of metabolomics study. (XLSX 27 kb)

Supplementary Table 2

Differentially expressed genes from RNA-seq. (XLSX 44 kb)

Supplementary Table 3

Differentially expressed proteins from proteomics. (XLSX 475 kb)

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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

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