Mitochondrial Degeneration – the Root of Skeletal Muscle Atrophy

项目总结 肌肉萎缩是许多慢性疾病的标志，会导致功能受损和质量下降 生命的质量。然而，目前预防肌肉萎缩的干预措施并不完全有效。因此，a 仍有必要充分阐明肌肉萎缩的机制。我们有证据表明他的肌肉萎缩 严重肥胖与线粒体生物发生和内容改变相关，并已获得证据 癌症恶病质(CC)和废用性肌肉萎缩的线粒体质量控制失调。我们的预赛 CC的APC(Min/+)小鼠模型中的数据表明线粒体质量控制发生了紊乱 恶病质发病前，线粒体生物发生和融合受损所致。因此，线粒体 紊乱可能会引发肌肉萎缩。事实上，我们最近的证据表明刘易斯·隆 肿瘤植入(LLC)提示线粒体退化在肿瘤后2周就开始了 植入，而身体和肌肉直到4周后才出现质量下降，因此，提示线粒体 排列紊乱在肌肉萎缩中很常见，可能先于肌肉萎缩。然而，无论这是不是 这些线粒体退行性变的共性和萎缩是真实的，目前尚不清楚。 萎缩与循环因子的改变有关，包括细胞因子和其他多肽。近期 我们实验室的初步证据表明，导致线粒体退化的分泌性因素，如 LLC细胞培养上清液处理C2C12心肌细胞可引起线粒体变性。然而， 目前尚不清楚这种影响的程度以及是什么因素促成了这种影响。此外，我们还报告了pGC-1α 足以促进线粒体的质量控制过程，而线粒体的活性氧物种 (ROS)可与致畸基因的诱导有关。因此，我们将确定是否促进线粒体 质量可以通过使用pGC-1α和线粒体过氧化氢酶(MCAT，线粒体ROS)来缓解肌肉萎缩 清道夫)转基因小鼠试图防止肌肉萎缩。我们的中心假设是：线粒体 由血源性因素引起的排列紊乱是肌肉发育的始动事件。 多种情况下的萎缩。 具体目标1.定义与废用和CC诱导的萎缩相关的线粒体紊乱。 具体目标2.确定提高线粒体质量是否足以缓解肌肉萎缩 在废用和CC中，并确定在萎缩中损害线粒体质量的新的血液传播因素。

PROJECT SUMMARY Muscle atrophy is a hallmark of many chronic diseases resulting in impaired function and reduced quality and quantity of life. However, current interventions to prevent muscle atrophy are not fully efficacious. Therefore, a critical need remains to fully elucidate mechanisms of muscle atrophy. We have evidence of muscle wasting in severe obesity associated with altered mitochondrial biogenesis and content and have acquired evidence of dysregulated mitochondrial quality control in cancer cachexia (CC) and disuse muscle atrophies. Our preliminary data in the Apc(Min/+) mouse model of CC suggest derangements in mitochondrial quality control occur before the onset of cachexia, initiated by impaired mitochondrial biogenesis and fusion. Hence, mitochondrial derangements may initiate development of muscle atrophies. In fact, our more recent evidence using Lewis Lung Carcinoma (LLC) implantation suggests mitochondrial degeneration begins as soon as 2 wks following tumor implantation while body and muscle mass loss do not occur until 4 wks post, thus, suggesting mitochondrial derangements are common among atrophies and may precede muscle atrophy. However, whether this is true among atrophies and the commonalities in these mitochondrial degenerations is unknown. Atrophies are associated with alterations in circulating factors including cytokines and other peptides. Recent preliminary evidence in our laboratory now implicates secreted factors inducing mitochondrial degeneration, as treatment of C2C12 myocytes with media from LLC cells induced mitochondrial degeneration. However, the extent of this impact and what factors mediate this impact are unknown. Additionally, we reported that PGC-1α is sufficient to promote mitochondrial quality control processes, while mitochondrial reactive oxygen species (ROS) can be associated with induction of atrogenes. Therefore, we will determine if promoting mitochondrial quality can alleviate muscle atrophies using PGC-1α and mitochondrial catalase (MCAT, mitochondrial ROS scavenger) transgenic mice to attempt to prevent muscle atrophy. Our central hypothesis is: mitochondrial derangements, induced by bloodborne factors, are an initiating event in the development of muscular atrophies in multiple conditions. Specific Aim 1. Define mitochondrial derangements associated with disuse and CC induced atrophies. Specific Aim 2. Determine if promotion of mitochondrial quality is sufficient to alleviate muscle atrophy in disuse and CC and ascertain novel bloodborne factors impairing mitochondrial quality in atrophy.