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Publication
Dissociation of muscle insulin sensitivity from exercise endurance in mice by
HDAC3 depletion.
Authors 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 BD, Molina H, Khurana TS, Rabinowitz JD, Lazar MA, Sun Z
Submitted By Submitted Externally on 8/17/2017
Status Published
Journal Nature medicine
Year 2017
Date Published
Volume : Pages 23 : 223 - 234
PubMed Reference 27991918
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.






Genes
SymbolDescription
Hdac3histone deacetylase 3

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