Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Department of Orthopedics, Second Xiangya Hospital, Central South University, Changsha, PR China.
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Free Radic Biol Med. 2021 Mar;165:299-311. doi: 10.1016/j.freeradbiomed.2021.01.047. Epub 2021 Feb 6.
Aging is accompanied by loss of muscle mass and force, known as sarcopenia. Muscle atrophy, weakness, and neuromuscular junction (NMJ) degeneration reminiscent of normal muscle aging are observed early in adulthood for mice deficient in Cu, Zn-superoxide dismutase (SOD, Sod1). Muscles of Sod1 mice also display impaired mitochondrial ATP production and increased mitochondrial reactive oxygen species (ROS) generation implicating oxidative stress in sarcopenia. Restoration of CuZnSOD specifically in neurons of Sod1 mice (SynTgSod1) prevents muscle atrophy and loss of force, but whether muscle mitochondrial function is preserved is not known. To establish links among CuZnSOD expression, mitochondrial function, and sarcopenia, we examined contractile properties, mitochondrial function and ROS production, intracellular calcium transients (ICT), and NMJ morphology in lumbrical muscles of 7-9 month wild type (WT), Sod1, and SynTgSod1 mice. Compared with WT values, mitochondrial ROS production was increased 2.9-fold under basal conditions and 2.2-fold with addition of glutamate and malate in Sod1 muscle fibers while oxygen consumption was not significantly altered. In addition, NADH recovery was blunted following contraction and the peak of the ICT was decreased by 25%. Mitochondrial function, ROS generation and calcium handling were restored to WT values in SynTgSod1 mice, despite continued lack of CuZnSOD in muscle. NMJ denervation and fragmentation were also fully rescued in SynTgSod1 mice suggesting that muscle mitochondrial and calcium handling defects in Sod1 mice are secondary to neuronal oxidative stress and its effects on the NMJ rather than the lack of muscle CuZnSOD. We conclude that intact neuronal function and innervation are key to maintaining excitation-contraction coupling and muscle mitochondrial function.
衰老伴随着肌肉质量和力量的丧失，即肌肉减少症。铜锌超氧化物歧化酶（SOD，Sod1）缺乏的小鼠在成年早期就观察到肌肉萎缩、无力和运动神经元肌接头（NMJ）退化，这些现象类似于正常的肌肉衰老。Sod1 小鼠的肌肉也表现出线粒体 ATP 产生受损和线粒体活性氧（ROS）生成增加，这表明氧化应激与肌肉减少症有关。神经元中特异性恢复 CuZnSOD（SynTgSod1）可防止肌肉萎缩和力量丧失，但肌肉线粒体功能是否得到保留尚不清楚。为了确定 CuZnSOD 表达、线粒体功能和肌肉减少症之间的联系，我们检查了 7-9 月龄野生型（WT）、Sod1 和 SynTgSod1 小鼠蚓状肌的收缩特性、线粒体功能和 ROS 生成、细胞内钙瞬变（ICT）和 NMJ 形态。与 WT 值相比，Sod1 肌纤维在基础条件下线粒体 ROS 生成增加了 2.9 倍，加入谷氨酸和苹果酸后增加了 2.2 倍，而耗氧量没有明显改变。此外，收缩后 NADH 恢复受损，ICT 峰值降低 25%。尽管肌肉中仍然缺乏 CuZnSOD，但 SynTgSod1 小鼠的线粒体功能、ROS 生成和钙处理恢复到 WT 值。SynTgSod1 小鼠的 NMJ 失神经和碎片化也得到了完全挽救，这表明 Sod1 小鼠的肌肉线粒体和钙处理缺陷是神经元氧化应激及其对 NMJ 的影响的结果，而不是肌肉缺乏 CuZnSOD 的结果。我们得出结论，完整的神经元功能和神经支配是维持兴奋-收缩偶联和肌肉线粒体功能的关键。
