Muscle atrophy is a significant moderator for disease prognosis; as such, interventions to mitigate disuse-induced muscle loss are imperative to improve clinical interventions. Mitochondrial deteriorations may underlie disuse-induced myopathies; therefore, improving mitochondrial quality may be an enticing therapeutic intervention. However, different mitochondrial-based treatments may have divergent impacts on the prognosis of disuse atrophy. Therefore, the purpose of this study was to investigate different mitochondria-centered interventions during disuse atrophy in hindlimb unloaded male and female mice. Methods: Male and female mice overexpressing PGC-1α (PGC-1α) or mitochondrially-targeted catalase (MCAT) and their respective wildtype (WT) littermate controls were hindlimb unloaded for 7 days to induce disuse atrophy or allowed normal ambulatory activity (cage control; CON). After designated interventions, animals were euthanized and tissues collected for measures of mitochondrial quality control and protein turnover. Results: While PGC-1α overexpression mitigated ubiquitin-proteasome activation (MuRF1 and Atrogin mRNA content), this did not correspond to phenotypic protections from disuse-induced atrophy. Rather, PGC-1α mice appeared to have a greater reliance on autophagic protein breakdown compared to WT. In MCAT mice, females exhibited a mitigated response to disuse atrophy; however, this effect was not noted in males. Despite these phenotypic differences, there were no clear cellular signaling differences between MCAT hindlimb unloaded females and MCAT fully loaded females. Conclusion: PGC-1α overexpression does not protect against phenotypic alterations during disuse atrophy but appears to shift catabolic pathways moderating atrophy. However, increased mitochondrially-targeted catalase activity appears to blunt disuse atrophy within highly oxidative muscles specifically in female mice.

中文翻译：

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改变线粒体质量的各个方面以改善废用性萎缩的肌肉骨骼结果。

肌肉萎缩是疾病预后的重要调节因素；因此，减轻废用性肌肉损失的干预措施对于改善临床干预措施势在必行。线粒体退化可能是废用性肌病的基础；因此，改善线粒体质量可能是一种诱人的治疗干预措施。然而，不同的基于线粒体的治疗可能对废用性萎缩的预后产生不同的影响。因此，本研究的目的是调查在后肢卸载的雄性和雌性小鼠的废用性萎缩期间不同的以线粒体为中心的干预措施。方法：过表达 PGC-1α (PGC-1α) 或线粒体靶向过氧化氢酶 (MCAT) 的雄性和雌性小鼠及其各自的野生型 (WT) 同窝对照小鼠后肢卸载 7 天以诱导废用性萎缩或允许正常的走动活动（笼控制；CON ）。在指定的干预措施后，动物被安乐死并收集组织以测量线粒体质量控制和蛋白质周转。结果：虽然 PGC-1α 过表达减轻了泛素蛋白酶体的激活（MuRF1 和 Atrogin mRNA 含量），但这并不对应于对废用诱导萎缩的表型保护。相反，与 WT 相比，PGC-1α 小鼠似乎更依赖自噬蛋白分解。在 MCAT 小鼠中，雌性对废用性萎缩的反应减弱；然而，在男性中没有注意到这种影响。尽管存在这些表型差异，但 MCAT 后肢卸载的雌性和 MCAT 完全加载的雌性之间没有明显的细胞信号差异。结论：PGC-1α 过表达不能防止废用性萎缩期间的表型改变，但似乎可以改变分解代谢途径以减轻萎缩。然而，线粒体靶向过氧化氢酶活性的增加似乎可以抑制雌性小鼠的高氧化性肌肉内的废用性萎缩。