过氧化物酶 3 过表达清除线粒体过氧化氢可减轻加速肌肉减少症小鼠模型中的收缩功能障碍和肌肉萎缩

Scavenging mitochondrial hydrogen peroxide by peroxiredoxin 3 overexpression attenuates

contractile dysfunction and muscle atrophy in a murine model of accelerated sarcopenia

Keywords：Aging, Hydrogen peroxide, Mitochondria, Peroxiredoxin3, Sarcopenia

关键词：老化、过氧化氢、线粒体、过氧化还原蛋白3、肌肉减少症

哺乳动物：小鼠
作者：Ahn Bumsoo, Ranjit Rojina, Kneis Parker, Xu Hongyang, Piekarz Katarzyna M, Freeman Willard M, Kinter Michael, Richardson Arlan, Ran Qitao, Brooks Susan V, Van Remmen Holly
出版期刊：《AGING CELL》（2022/2/1）

Abstract：

Age-related muscle atrophy and weakness, or sarcopenia, are significant contributors to compromised health and quality of life in the elderly. While the mechanisms driving this pathology are not fully defined, reactive oxygen species, neuromuscular junction (NMJ) disruption, and loss of innervation are important risk factors. The goal of this study is to determine the impact of mitochondrial hydrogen peroxide on neurogenic atrophy and contractile dysfunction. Mice with muscle-specific overexpression of the mitochondrial H2O2 scavenger peroxiredoxin3 (mPRDX3) were crossed to Sod1KO mice, an established mouse model of sarcopenia, to determine whether reduced mitochondrial H2O2 can prevent or delay the redox-dependent sarcopenia. Basal rates of H2O2 generation were elevated in isolated muscle mitochondria from Sod1KO, but normalized by mPRDX3 overexpression. The mPRDX3 overexpression prevented the declines in maximum mitochondrial oxygen consumption rate and calcium retention capacity in Sod1KO. Muscle atrophy in Sod1KO was mitigated by ~20% by mPRDX3 overexpression, which was associated with an increase in myofiber cross-sectional area. With direct muscle stimulation, maximum isometric specific force was reduced by ~20% in Sod1KO mice, and mPRDX3 overexpression preserved specific force at wild-type levels. The force deficit with nerve stimulation was exacerbated in Sod1KO compared to direct muscle stimulation, suggesting NMJ disruption in Sod1KO. Notably, this defect was not resolved by overexpression of mPRDX3. Our findings demonstrate that muscle-specific PRDX3 overexpression reduces mitochondrial H2O2 generation, improves mitochondrial function, and mitigates loss of muscle quantity and quality, despite persisting NMJ impairment in a murine model of redox-dependent sarcopenia.

文章摘要：

与年龄相关的肌肉萎缩和虚弱、或肌肉减少症，是导致老年人健康和生活质量受损的重要因素。虽然驱动这种病理的机制尚未完全确定，但活性氧、神经肌肉接头 (NMJ) 破坏和神经支配丧失是重要的风险因素。本研究的目的是确定线粒体过氧化氢对神经源性萎缩和收缩功能障碍的影响。将线粒体 H2O2 清除剂 peroxiredoxin3 (mPRDX3) 的肌肉特异性过表达的小鼠与已建立的肌肉减少症小鼠模型 Sod1KO 小鼠进行杂交，以确定减少的线粒体 H2O2 是否可以预防或延迟氧化还原依赖性肌肉减少症。从 Sod1KO 分离的肌肉线粒体中 H2O2 生成的基础速率升高，但通过 mPRDX3 过表达标准化。 过表达mPRDX3阻止了 Sod1KO 中最大线粒体耗氧率和钙保留能力的下降。通过过表达 mPRDX3 ，Sod1KO 中的肌肉萎缩减轻了约 20%，这与肌纤维横截面积的增加有关。通过直接肌肉刺激，Sod1KO 小鼠的最大等长比力降低了约 20%，并且过表达mPRDX3 保留了野生型的比力水平。与直接肌肉刺激相比，Sod1KO 加剧了神经刺激引起的力量下降，表明 Sod1KO 中的 NMJ 中断。值得注意的是，这种缺陷并没有通过 mPRDX3 的过表达来解决。我们的研究结果表明，尽管在氧化还原依赖性肌肉减少症小鼠模型中持续存在 NMJ 损伤，但过表达肌肉特异性 PRDX3 减少了线粒体 H2O2 的生成，改善了线粒体功能，并减轻了肌肉数量和质量的损失。

点击链接即可查看和下载文章：https://onlinelibrary.wiley.com/doi/10.1111/acel.13569

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