Mechanism of mitochondria-induced proteostatic signaling and progressive muscle atrophy during aging.

肌肉萎缩(或消瘦)的定义是肌纤维大小和数量减少，这会增加发病率和 死亡率和生活质量下降。肌肉萎缩的机制之一是蛋白抑制剂的丧失。 平衡。当蛋白质降解超过合成时，蛋白质含量就会减少，从而缩小肌纤维的尺寸。 和肌肉质量。蛋白质合成和降解之间的平衡是如何被扰乱的 未知的衰老骨骼肌。线粒体功能障碍在骨骼肌萎缩中起重要作用 在许多疾病条件下和正常衰老期间，潜在机制仍然很差 明白了。氧化磷酸化的扰动和随后的活性氧的增加 物种生产，统称为“生物能量缺陷”，已经被认为是导致肌肉损失的原因。 然而，越来越多的证据表明，大量的生物能量缺乏和氧化 压力不足以导致肌肉萎缩。因此，如果线粒体功能障碍确实导致 肌肉损失，它可能涉及生物能量独立的因素。陈实验室最近发现各种 线粒体损伤的形式可以减少线粒体蛋白的输入。这会导致蛋白质平衡应激在 胞浆，称为线粒体前体过度积累应激(MPOS)，随后是细胞整体重塑 蛋白质平衡。我们最近培育了一个适度过度表达线粒体的转基因小鼠系。 内膜蛋白，ANT1。我们发现ANT1诱导的线粒体蛋白输入应激导致 进行性肌肉萎缩，伴有线粒体呼吸减少。然而，无论肌肉是否 萎缩是由生物能量缺乏或生物能量独立应激源引起的，目前尚不清楚。 有趣的是，rna-seq分析显示了整合应激反应(Isr)的强健激活，这在 TURN抑制全球蛋白质合成并激活自噬。ISR激活在组织中普遍存在 来源于线粒体疾病患者。使用这一独特的鼠标模型，我们建议确定 线粒体诱导肌肉萎缩和ISR激活的分子机制。在目标1中，我们将确定 线粒体蛋白输入应激导致肌肉萎缩的机制。在目标2中，我们将 确定ISR激活是否保护骨骼肌免受肌纤维死亡和肌病的影响 MPOS。这个项目的长期目标是了解不依赖于生物能量学的线粒体应激 在正常和非正常衰老中，信号促进慢性肌肉萎缩。这样做的结果 应用可能有助于建立治疗线粒体诱导肌肉的非生物能量学途径 疾病，可能还有石棺减少症。

Muscle atrophy (or wasting) is defined by reduced myofiber size and number, which increases morbidity and mortality and decreases quality of life. One of the mechanisms of muscle atrophy is the loss of proteostatic balance. When protein degradation exceeds synthesis, protein content is decreased to reduce myofiber size and muscle mass. How the balance between protein synthesis and degradation is disturbed in diseased and aged skeletal muscle in unknown. Mitochondrial dysfunction plays an important role in skeletal muscle atrophy under many disease conditions and during normative aging, with the underlying mechanism remaining poorly understood. Perturbations in oxidative phosphorylation and the subsequent increase in reactive oxygen species production, collectively termed “bioenergetic defects”, have been proposed to drive muscle loss. However, accumulating evidence suggests that substantial levels of bioenergetic deficiency and oxidative stress are insufficient to cause muscle wasting. Therefore, if mitochondrial dysfunction does indeed result in muscle loss, it may involve bioenergetically independent factors. The Chen lab recently found that various forms of mitochondrial damage can reduce mitochondrial protein import. This causes proteostatic stress in the cytosol, termed mitochondrial Precursor Overaccumulation Stress (mPOS), followed by global remodeling of proteostasis. We recently generated a transgenic mouse line that moderately overexpresses the mitochondrial inner membrane protein, Ant1. We found that Ant1-induced mitochondrial protein import stress causes progressive muscle atrophy, accompanied by reduction of mitochondrial respiration. However, whether muscle atrophy is caused by bioenergetic deficiency or bioenergetic-independent stressors remains unknown. Interestingly, RNA-seq analysis revealed a robust activation of the integrated stress response (ISR), which in turn represses global protein synthesis and activates autophagy. ISR activation is commonly found in tissues derived from patients with mitochondrial disease. Using this unique mouse model, we propose to determine the molecular mechanisms of mitochondria-induced muscle atrophy and ISR activation. In Aim 1, we will determine the mechanism by which mitochondrial protein import stress induces muscle wasting. In Aim 2, we will determine whether ISR activation protects skeletal muscle from myofiber death and myopathy in the setting of mPOS. The long-term goal of this project is to understand how bioenergetics-independent mitochondrial stress signaling promotes chronic muscle wasting in normative and non-normative aging. The results of this application may help establish a bioenergetics-independent pathway for treating mitochondria-induced muscle disease and possibly sarcopenia.