Exercise improves high-fat diet-induced metabolic disorder by promoting HDAC5 degradation through the ubiquitin–proteasome system in skeletal muscle
Exercise improves high-fat diet-induced metabolic disorder by promoting HDAC5 degradation through the ubiquitin–proteasome system in skeletal muscle
复制标题
运动通过骨骼肌中的泛素蛋白酶体系统促进 HDAC5 降解，从而改善高脂肪饮食引起的代谢紊乱
DOI：
10.1139/apnm-2022-0174
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Niu Yanmei
中科院分区：
文献类型：
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作者：
Huang Song;Zheng Xinyue;Zhang Xinyu;Jin Zhe;Liu Sujuan;Fu Li;Niu Yanmei
组蛋白脱乙酰酶4/5(HDAC4/5)是调节代谢基因表达的关键基因，AMPKMuRF1-2调节运动过程中HDAC4/5的活性和α的表达。本研究以野生型和AMPKα-2−/−小鼠为研究对象，探讨运动过程中AMPK-α-2和HDAC4/5表达之间的潜在调控关系。首先，用高脂饲料喂养C57BL/6J小鼠8周，观察高脂饲料对小鼠骨骼肌代谢及HDAC4/5表达的影响。然后，我们在野生型和AMPKα2−/−小鼠身上进行了为期6周的跑步机运动。运动后检测腓肠肌和比目鱼肌中HDAC4/5的表达。测定柠檬酸合成酶活性和参与骨骼肌氧化过程的蛋白质。为了确定HDAC4/5与骨骼肌氧化能力的关系，在沉默HDAC4/5后，测定了柠檬酸合成酶的活性。此外，还研究了HDAC5的泛素化以及MuRF1与HDAC5的关系。结果表明，6周运动提高骨骼肌氧化能力，降低HDAC4/5在比目鱼肌中的表达。HDAC5沉默增加了C2C12细胞的氧化能力。MG132抑制蛋白酶体可阻断由MuRF1-泛素-蛋白酶体系统介导的运动诱导的HDAC5降解。然而，泛素-蛋白酶体系统(UPS)并不是运动诱导的HDAC4降解的主要原因。运动可上调野生型小鼠MURF1-HDAC5的关联性，但对AMPKα2−/−小鼠无明显影响。结果表明，6周运动通过UPS、MuRF1介导的HDAC5泛素化，提高比目鱼肌的氧化能力，促进HDAC5的降解。尽管AMPKα2在调节MuRF1表达和HDAC5泛素化方面起到了部分作用，但运动诱导的HDAC5降解并不完全依赖于AMPKα2。
Histone deacetylase 4/5 (HDAC4/5) are essential for regulating metabolic gene expression; AMPKα2 regulates HDAC4/5 activity and the expression of MuRF1 during exercise. In this study, we usedwild-typeandAMPKα2−/−mice to explore the potential regulatory relationship between AMPKα2 and HDAC4/5 expression during exercise. Firstly, we fed C57BL/6J mice with high-fat diet for 8 weeks to assess the effects of high-fat diet on skeletal muscle metabolism and HDAC4/5 expression. We then performed a 6-week treadmill exercise on bothwild-typeandAMPKα2−/−mice. After exercise, the expressions of HDAC4/5 were examined in both gastrocnemius and soleus. The citrate synthase activity and proteins involved in skeletal muscle oxidative process were assessed. To determine the relationship of HDAC4/5 and skeletal muscle oxidative capacity, citrate synthase activity was assessed after silencing HDAC4/5. Moreover, HDAC5 ubiquitination and the association of MuRF1 to HDAC5 were also investigated. Our results showed that 6-week exercise increased the skeletal muscle oxidative capacity and decreased HDAC4/5 expression only in soleus. HDAC5 silencing increased C2C12 cell oxidative capacity. Proteasome inhibition by MG132 abolished exercise-induced HDAC5 degradation mediated by MuRF1–ubiquitin–proteasome system. However, the ubiquitin–proteasome system (UPS) did not dominantly account for exercise-induced HDAC4 degradation. Exercise upregulated MuRF1–HDAC5 association inwild-typemice but not inAMPKα2−/−mice. Our results revealed that 6-week exercise increased the skeletal muscle oxidative capacity and promoted HDAC5 degradation in soleus through the UPS, MuRF1-mediated HDAC5 ubiquitination. Although AMPKα2 played a partial role in regulating MuRF1 expression and HDAC5 ubiquitination, exercise-induced HDAC5 degradation did not fully depend on AMPKα2.