Mechanism of Mitochondria-induced Progressive Muscle Wasting

肌肉萎缩(或萎缩)的定义是肌纤维的大小、数量和强度减少。它发生在衰老过程中， 肌肉停用、失神经、癌症、艾滋病、糖尿病和心力衰竭，这些都会增加虚弱、发病率 和死亡率。在生理条件下，肌纤维的大小是由蛋白质之间的平衡来维持的 合成和降解。蛋白质平衡是如何在各种萎缩条件下不平衡的？ 明白了。线粒体功能障碍被认为与进行性肌肉萎缩有关。多数 线粒体在能量产生、氧化应激和细胞凋亡中的作用一直是研究的重点。 然而，最近的研究表明，相当程度的生物能量缺乏和氧化应激是 不足以导致肌纤维萎缩和进行性肌肉萎缩。如果线粒体应激导致 肌肉萎缩，这必须涉及到一种新的机制。我们最近培育了一只转基因小鼠 适度过表达ANT1的品系，ANT1是腺嘌呤核苷酸易位酶的肌肉/心脏亚型 参与跨线粒体内膜的ATP/ADP交换(IMM)，以模拟 最常见的肌肉疾病称为面肩肩周性肌营养不良症(FSHD)。我们发现 ANT1转基因小鼠的肌纤维尺寸变小，肌肉质量逐渐减少。我们的预赛 研究支持这样的观点，除了中度的生物能量缺陷外，ANT1的过度表达还会导致 胞浆中的蛋白抑制应激。我们推测ANT1超载可能干扰了蛋白质的输入和 引起线粒体前体过度积累应激(MPOS)--一种新的线粒体诱导应激 以未进口的蛋白质在细胞质中过度积累为特征。我们还建议 蛋白抑制剂对mPOS的适应可能会慢性减少蛋白质合成并增加蛋白质 退化，最终导致肌肉萎缩。在本应用程序中，我们将通过以下方式测试这些假设 提出了以下具体目标。(1)我们将测试适度的ANT1过度表达是否足够 在胞浆中诱导蛋白抑制应激。(2)我们将确定胞浆途径对 对未进口的线粒体蛋白进行分选。(3)我们将检验ANT1诱导肌肉的假说 萎缩是由于蛋白质合成减少和/或蛋白酶体和自噬活性增加所致， 作为对mPOS的应激反应而触发。这个项目的成功可能会导致一部小说的发现 线粒体影响肌肉质量动态平衡的机制。结果可能会直接 对理解几种涉及ANT1过度表达的疾病的影响，包括FSHD， 扩张型心肌病和雷特综合征。最后，mPOS模型在小鼠身上的验证可能会 对于理解其他影响蛋白质输入的线粒体疾病具有广泛的意义。

Muscle wasting (or atrophy) is defined by reduced myofiber size, number and strength. It occurs in aging, muscle disuse, denervation, cancer, AIDS, diabetes and cardiac failure, which increases frailty, morbidity and mortality. Under physiological conditions, myofiber size is maintained by a balance between protein synthesis and degradation. How proteostasis is unbalanced under various atrophying conditions is poorly understood. Mitochondrial dysfunction has been proposed to contribute to progressive muscle atrophy. Most studies have been focused on the role of mitochondria in energy production, oxidative stress and apoptosis. However, recent studies showed that considerable levels of bioenergetic deficiency and oxidative stress are not sufficient to cause myofiber shrinkage and progressive muscle wasting. If mitochondrial stress causes muscle wasting, it would have to involve a novel mechanism. We recently generated a transgenic mouse line that moderately overexpresses Ant1, the muscle/heart isoform of adenine nucleotide translocase involved in ATP/ADP exchange across the inner membrane of mitochondria (IMM), to model one of the most common muscle diseases known as Facioscapulohumeral Muscular Dystrophy (FSHD). We found that the ANT1-transgenic mice have reduced myofiber size and progressively lose muscle mass. Our preliminary studies support the idea that, in addition to moderate bioenergetic defect, ANT1-overexpression causes proteostatic stress in the cytosol. We hypothesize that Ant1 overloading may disturb protein import and cause mitochondrial Precursor Overaccumulation Stress (mPOS), a novel mitochondria-induced stress characterized by the overaccumulation of unimported proteins in the cytosol. We also propose that proteostatic adaptation to mPOS may chronically reduce protein synthesis and increase protein degradation, which ultimately leads to muscle wasting. In this application, we will test these hypotheses by proposing the following specific aims. (1) We will test whether moderate ANT1 overexpression is sufficient to induce proteostatic stress in the cytosol. (2) We will identify cytosolic pathways that are important for the triage of unimported mitochondrial proteins. (3) We will test the hypothesis that Ant1-induced muscle atrophy results from reduced protein synthesis and/or increased proteasomal and autophagy activities, triggered as stress responses to mPOS. Success of the project may lead to the discovery of a novel mechanism by which mitochondria affect muscle mass homeostasis. The results could have direct implications for the understanding of several diseases that involve ANT1 overexpression, including FSHD, dilated cardiomyopathy and Rett syndrome. Finally, the validation of the mPOS model in mice could have broad implications for the understanding of other mitochondrial disorders that affect protein import.