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Abstract：
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.
摘要：
衰老伴随着肌肉质量和力量的损失，称为肌少症。肌肉萎缩,弱点,和神经肌肉接头（NMJ）变性让人想起正常的肌肉老化在成年早期观察到缺乏铜的小鼠，锌-超氧化物歧化酶（SOD，Sod1-/-）。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）产生增加，这与肌肉减少症中的氧化应激有关。特别是在Sod1-/-小鼠（SynTgSod1-/-）的神经元中恢复CuZnSOD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。为了建立CuZnSOD表达之间的联系，线粒体功能，和肌少症,我们检查了收缩特性，线粒体功能和ROS产生，细胞内钙瞬变（ICT），7-9个月野生型（WT）的腰肌和NMJ形态，Sod1-/-,和SynTgSod1-/-小鼠。与WT值相比，线粒体ROS的产生在基础条件下增加2.9倍,在Sod1-/-肌纤维中添加谷氨酸和苹果酸则增加2.2倍,而耗氧量没有显著改变.此外,收缩后，NADH的恢复减弱，ICT的峰值降低了25％。线粒体功能,在SynTgSod1-/-小鼠中，ROS产生和钙处理恢复到WT值，尽管肌肉中持续缺乏CuZnSOD。在SynTgSod1-/-小鼠中，NMJ的神经支配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继发于神经元氧化应激及其对NMJ的影响，而不是缺乏肌肉CuZnSOD。我们得出的结论是，完整的神经元功能和神经支配是维持兴奋-收缩耦合和肌肉线粒体功能的关键。
