Skeletal muscle mitochondrial respiration in a model of age-related osteoarthritis is impaired after dietary rapamycin.
Skeletal muscle mitochondrial respiration in a model of age-related osteoarthritis is impaired after dietary rapamycin.
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DOI：
10.1016/j.exger.2021.111579
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发表时间：
2021-11
影响因子：
3.9
通讯作者：
Konopka AR
中科院分区：
文献类型：
--
作者：
Elliehausen CJ;Minton DM;Nichol AD;Konopka AR
骨骼肌线粒体功能的下降与膝关节骨关节炎（OA）期间骨骼肌大小和功能的丧失有关。我们最近报道了12周的饮食雷帕霉素（Rap, 14ppm），加或不加二甲双胍（Met, 1000ppm），增加了雄性Dunkin Hartley （DH）豚鼠的血糖和OA严重程度，这是一种自然发生的年龄相关性OA模型。本研究的目的是确定饮食Rap和Rap+Met后OA严重程度的增加是否伴随骨骼肌线粒体功能受损。线粒体呼吸和过氧化氢（H2O2）排放通过高分辨率呼吸测定法和荧光测定法在渗透性肌纤维中进行评估，使用饱和剂量或ADP滴定。Rap和Rap+Met降低复合体I （CI）相关呼吸，并倾向于增加ADP敏感性，与先前在终末期OA患者中的发现一致。CI相关呼吸的减少伴随着CI蛋白丰度的降低。Rap和Rap+Met没有改变线粒体H2O2的排放。Rap与Rap+Met的线粒体功能没有差异，这表明Rap可能驱动了线粒体功能的变化。这是首次研究Rap和Rap+Met延长寿命治疗如何影响与年龄相关的OA模型中的骨骼肌线粒体。总的来说，我们的数据表明，在OA严重程度较高的DH豚鼠中，含或不含Met的Rap会抑制ci相关能力，并增加ADP敏感性。
A decline in skeletal muscle mitochondrial function is associated with the loss of skeletal muscle size and function during knee osteoarthritis (OA). We have recently reported that 12-weeks of dietary rapamycin (Rap, 14ppm), with or without metformin (Met, 1000ppm), increased plasma glucose and OA severity in male Dunkin Hartley (DH) guinea pigs, a model of naturally occurring, age-related OA. The purpose of the current study was to determine if increased OA severity after dietary Rap and Rap+Met was accompanied by impaired skeletal muscle mitochondrial function. Mitochondrial respiration and hydrogen peroxide (H2O2) emissions were evaluated in permeabilized muscle fibers via high-resolution respirometry and fluorometry using either a saturating bolus or titration of ADP. Rap and Rap+Met decreased complex I (CI)-linked respiration and tended to increase ADP sensitivity, consistent with previous findings in patients with end-stage OA. The decrease in CI-linked respiration was accompanied with lower CI protein abundance. Rap and Rap+Met did not change mitochondrial H2O2 emissions. There were no differences between mitochondrial function in Rap versus Rap+Met suggesting that Rap was likely driving the change in mitochondrial function. This is the first inquiry into how lifespan extending treatments Rap and Rap+Met can influence skeletal muscle mitochondria in a model of age-related OA. Collectively, our data suggest that Rap with or without Met inhibits CI-linked capacity and increases ADP sensitivity in DH guinea pigs that have greater OA severity.
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