Department of Medicine, Division of Geriatrics and Gerontology, University of Wisconsin-Madison, United States of America; Geriatric Research, Education, and Clinical Center, William S. Middleton Memorial Veterans Hospital, United States of America; Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, United States of America.
Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, United States of America.
Exp Gerontol. 2021 Nov;155:111579. doi: 10.1016/j.exger.2021.111579. Epub 2021 Sep 30.
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, 14 ppm), with or without metformin (Met, 1000 ppm), 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 (HO) 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 HO 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.
骨骼肌线粒体功能的下降与膝骨关节炎（OA）期间骨骼肌大小和功能的丧失有关。我们最近报道，12 周的雷帕霉素（Rap，14 ppm）饮食，无论是否联合二甲双胍（Met，1000 ppm），都会增加雄性 Dunkin Hartley（DH）豚鼠的血浆葡萄糖和 OA 严重程度，DH 豚鼠是一种自然发生的、与年龄相关的 OA 模型。本研究的目的是确定 Rap 和 Rap+Met 饮食后 OA 严重程度增加是否伴有骨骼肌线粒体功能受损。通过高分辨率呼吸计和荧光计，使用饱和脉冲或 ADP 滴定，在透化肌纤维中评估线粒体呼吸和过氧化氢（HO）排放。Rap 和 Rap+Met 降低了与复合物 I（CI）相关的呼吸作用，并倾向于增加 ADP 敏感性，这与终末期 OA 患者的先前发现一致。CI 相关呼吸的下降伴随着 CI 蛋白丰度的降低。Rap 和 Rap+Met 并没有改变线粒体 HO 的排放。Rap 与 Rap+Met 之间的线粒体功能没有差异，这表明 Rap 很可能是导致线粒体功能变化的原因。这是首次研究在与年龄相关的 OA 模型中，延长寿命的治疗方法 Rap 和 Rap+Met 如何影响骨骼肌线粒体。总的来说，我们的数据表明，Rap 无论是否与 Met 联合使用，都会抑制 DH 豚鼠 CI 相关的容量，并增加 ADP 敏感性，而这些豚鼠的 OA 严重程度更大。
