Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion.
Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion.
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DOI：
10.1038/nm.4245
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发表时间：
2017-03
期刊：
影响因子：
82.9
通讯作者：
Sun Z
中科院分区：
文献类型：
--
作者：
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
2型糖尿病（T2D）和胰岛素抵抗与肌肉中葡萄糖利用率降低和运动表现不佳有关。在这里，我们发现表观基因组修饰子组蛋白去乙酰化酶3 （HDAC3）的消耗，特别是在骨骼肌中，导致小鼠严重的全身胰岛素抵抗，但显著提高运动耐力和肌肉疲劳抵抗，尽管减少肌肉力量。这种看似矛盾的表型是由于在hdac3缺失的肌肉中，葡萄糖利用率较低，脂质氧化较大，这是由AMP脱氨酶3 （Ampd3）和支链氨基酸分解代谢驱动的折回反应激活引起的燃料开关。这些发现强调了氨基酸分解代谢在肌肉疲劳和T2D发病机制中的关键作用。此外，由于骨骼肌中HDAC3的基因组占用是由生物钟控制的，这些结果描绘了一种表观基因组调节机制，通过生物钟控制骨骼肌生物能量学。这些发现表明，在一天中的特定时间进行体育锻炼或以HDAC3为靶点的药物治疗可能会改变全身燃料代谢和运动表现。
Type 2 diabetes (T2D) and insulin resistance are associated with reduced glucose utilization in the muscle and poor exercise performance. Here we find that depletion of an epigenome modifier, histone deacetylase 3 (HDAC3), specifically in skeletal muscle causes severe systemic insulin resistance in mice, but markedly enhances exercise endurance and muscle fatigue resistance, 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 branched-chain amino acid catabolism. These findings highlight the pivotal role of amino acid catabolism in muscle fatigue and T2D 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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影响因子：
2.7
作者：
Cheng J;Morisaki H;Toyama K;Sugimoto N;Shintani T;Tandelilin A;Hirase T;Holmes EW;Morisaki T
通讯作者：
Morisaki T
影响因子：
29
作者：
Hatori M;Vollmers C;Zarrinpar A;DiTacchio L;Bushong EA;Gill S;Leblanc M;Chaix A;Joens M;Fitzpatrick JA;Ellisman MH;Panda S
通讯作者：
Panda S
DOI：
10.1126/science.1198125
发表时间：
2011-03-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Feng D;Liu T;Sun Z;Bugge A;Mullican SE;Alenghat T;Liu XS;Lazar MA
通讯作者：
Lazar MA
影响因子：
7.7
作者：
Kelley, DE;Mandarino, LJ
通讯作者：
Mandarino, LJ
影响因子：
15.9
作者：
Kim, JK;Michael, MD;Shulman, GI
通讯作者：
Shulman, GI