Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice.
Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice.
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DOI：
10.1002/jcsm.12794
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Ahn J
中科院分区：
文献类型：
--
作者：
Lee H;Ha TY;Jung CH;Nirmala FS;Park SY;Huh YH;Ahn J
尽管越来越多的证据表明，骨骼肌线粒体功能障碍与胰岛素抵抗(IR)并存，但线粒体功能障碍与IR发病机制之间尚无明确的因果关系。在这项研究中，确定了线粒体在IR发育中的确切作用。6周龄C57BL/6小鼠以高脂饲料喂养2周诱导急性IR或24周诱导慢性IR(n=8)。为了表征线粒体的功能，我们测量了腓肠肌和肝脏组织的柠檬酸合成酶活性、ATP含量、线粒体DNA(MtDNA)含量和耗氧率。我们用线粒体分裂抑制物1(mdivi-1)对急性IR小鼠进行了腹腔注射，并检测了线粒体适应性反应，如线粒体吞噬、线粒体未折叠蛋白反应(UPRmt)和氧化应激(n=6)。急性IR与线粒体功能受损的发生是一致的，包括骨骼肌中柠檬酸合成酶活性(−37.8%，P<0.01)、三磷酸腺苷生成(−88.0%，P<0.01)、线粒体DNA(−53.1%，P<0.01)和线粒体呼吸(−52.2%，最大呼吸，P<0.05)。给予mdivi-1通过增加线粒体功能来减弱IR的发展(线粒体DNA含量+58.5%，P<0.01；柠檬酸合成酶活性4.06±0.69至5.84±0.95pmol/分钟/mg，P<0.05；最大呼吸13.06±0.70至34.87±0.70 pmol/min/g，P<0.001)。Western印迹分析显示急性IR导致肌肉组织自噬(有丝分裂吞噬)和UPRmt诱导增加。这种适应性反应被mdivi-1抑制，从而减少了急性IR期间骨骼肌线粒体的氧化应激。急性IR诱导线粒体氧化应激，损伤骨骼肌线粒体功能。改善线粒体功能对治疗急性IR具有重要潜力。
Although mounting evidence indicates that insulin resistance (IR) co‐occurs with mitochondrial dysfunction in skeletal muscle, there is no clear causal link between mitochondrial dysfunction and IR pathogenesis. In this study, the exact role of mitochondria in IR development was determined. Six‐week‐old C57BL/6 mice were fed a high‐fat diet for 2 weeks to induce acute IR or for 24 weeks to induce chronic IR (n = 8 per group). To characterize mitochondrial function, we measured citrate synthase activity, ATP content, mitochondrial DNA (mtDNA) content, and oxygen consumption rate in gastrocnemius and liver tissues. We intraperitoneally administered mitochondrial division inhibitor 1 (mdivi‐1) to mice with acute IR and measured mitochondrial adaptive responses such as mitophagy, mitochondrial unfolded protein response (UPRmt), and oxidative stress (n = 6 per group). Acute IR occurred coincidently with impaired mitochondrial function, including reduced citrate synthase activity (−37.8%, P < 0.01), ATP production (−88.0%, P < 0.01), mtDNA (−53.1%, P < 0.01), and mitochondrial respiration (−52.2% for maximal respiration, P < 0.05) in skeletal muscle but not in liver. Administration of mdivi‐1 attenuated IR development by increasing mitochondrial function (+58.5% for mtDNA content, P < 0.01; 4.06 ± 0.69 to 5.84 ± 0.95 pmol/min/mg for citrate synthase activity, P < 0.05; 13.06 ± 0.70 to 34.87 ± 0.70 pmol/min/g for maximal respiration, P < 0.001). Western blot analysis showed acute IR resulted in increased autophagy (mitophagy) and UPRmt induction in muscle tissue. This adaptive response was inhibited by mdivi‐1, which reduced the mitochondrial oxidative stress of skeletal muscle during acute IR. Acute IR induced mitochondrial oxidative stress that impaired mitochondrial function in skeletal muscle. Improving mitochondrial function has important potential for treating acute IR.
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影响因子：
2.5
作者：
Kugler BA;Deng W;Duguay AL;Garcia JP;Anderson MC;Nguyen PD;Houmard JA;Zou K
通讯作者：
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影响因子：
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作者：
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影响因子：
2.9
作者：
Humphries, KM;Yoo, Y;Szweda, LI
通讯作者：
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