骨骼肌线粒体蛋白酶LONP1在缺少运动导致的肌肉衰减中的调控功能与作用机制

肌肉健康是健康体魄的根本保证，肌肉衰减在老年人中发病率高达30%，肌肉衰减导致老年人行动不便，还会引发肥胖、糖尿病等代谢综合征，严重影响老年人健康水平和生活质量。线粒体质量对于骨骼肌功能维持及其应答生理病理反应所必需，肌肉线粒体质量如何控制及在肌萎缩中的功能却十分不清楚。我们曾发现骨骼肌线粒体自噬对于骨骼肌代谢功能维持和运动能力至关重要。本课题的前期研究表明线粒体蛋白稳态关键调控因子LONP1能够响应肌肉废用信号，在缺乏运动诱导的肌肉衰减早期显著下调。此外，骨骼肌特异性LONP1敲除小鼠导致线粒体蛋白稳态失衡，严重影响肌肉含量及运动能力。因此，我们提出：线粒体蛋白酶LONP1能响应肌肉废用信号，在肌肉衰减发生发展中发挥重要功能。为证实这一假设我们将分别从整体，细胞和线粒体亚细胞水平阐明LONP1介导的线粒体蛋白质稳态控制在肌肉衰减发生发展中的作用与机制，为肌肉衰减的防治新途径提供实验依据。

Healthy muscles constitute the fundamental basis of a healthy body. The incidence rate of sarcopenia caused by aging is as high as 30% among the olds, sarcopenia causes physical inactivity to the elderly, and also causes metabolic syndrome such as obesity and diabetes, which seriously affects their quality of health and life. Mitochondrial quality control is crucial for skeletal muscle function and its response to physiological or pathological stimulations. However, how to control the quality of muscle mitochondria and its function in muscular atrophy remains unclear. We have previously demonstrated that skeletal muscle mitophagy play a crucial role in muscle metabolism and exercise capacity. In this study, we have found that the mitochondrial protein homeostasis key regulator LONP1 significantly decreased in the early stage of muscular atrophy caused by muscle disuse in mice. Moreover, loss of mice muscle LONP1 resulted in mitochondrial protein accumulation, mitochondrial protein homeostasis disturbed, muscle mass and exercise capacity significantly decreased. Therefore, we propose that physical inactivity associated mitochondrial protease LONP1 loss is crucial for regulating the development of sarcopenia. To verify this hypothesis, we will analyze a series of animal model with physiological, molecular and cellular methods to elucidate the role of LONP1 mediated mitochondrial quality control in the occurrence and development of sarcopenia, which will providing experimental instructions for new therapeutic strategies of sarcopenia.