Regulation of skeletal muscle apoptotic signaling and programmed cell death

细胞凋亡是细胞死亡的一种形式，在控制组织发育和体内平衡中起重要作用；然而，功能障碍发生在许多疾病中。线粒体在产生能量、改变活性氧（ROS）水平和释放直接促进细胞凋亡的因子方面发挥着重要的作用，是细胞生存和死亡的重要介质。最近的证据表明，骨骼肌细胞凋亡增加导致肌肉萎缩，并可能导致与神经肌肉疾病、心血管疾病和衰老相关的功能缺陷。骨骼肌具有显著的细胞适应能力，包括线粒体生物发生/含量的改变，以响应生理和病理生理刺激。独立研究表明，线粒体含量的减少会增加氧化应激和细胞凋亡，发生在几种骨骼肌疾病和衰老中。相反，体育活动可以增加线粒体的生物发生，促进ROS的去除，减少骨骼肌的细胞凋亡。总的来说，这些研究表明线粒体含量可能是决定细胞功能和存活的重要因素。然而，线粒体含量改变对氧化应激和细胞凋亡的直接影响尚未在包括骨骼肌在内的任何细胞类型中得到研究。拟议的研究将使用几种不同的方法在体外（肌肉和非肌肉细胞）和体内（骨骼肌）改变线粒体含量。使用最先进的方法，我们将全面研究细胞凋亡和氧化应激（在基础状态和响应细胞应激）在线粒体含量低或高的条件下是如何改变的。此外，定期体育活动（诱导肌肉中的线粒体生物发生）的功效将被评估为抑制骨骼肌氧化应激、细胞凋亡和萎缩的策略，以应对化学应激和肌肉萎缩的病理生理状况。最终，这项研究的发现可能对理解调节骨骼肌凋亡的分子机制和运动时发生的生理适应具有重要意义。

Apoptosis is a form of cell death that plays an important role in controlling tissue development and homeostasis; however, dysfunction occurs in numerous diseases. Mitochondria are important mediators of cell survival and death given their role in producing energy, altering the levels of damaging reactive oxygen species (ROS), and releasing factors that directly promote apoptosis. Recent evidence suggests that increased apoptosis in skeletal muscle contributes to the muscle atrophy and possibly the functional deficiencies associated with neuromuscular disorders, cardiovascular disease, and aging. Skeletal muscle has the remarkable ability to undergo various cellular adaptations including alterations in mitochondrial biogenesis/content in response to physiological and pathophysiological stimuli. Independent studies have shown that reduced mitochondrial content along will increased oxidative stress and apoptosis occurs in several skeletal muscle disorders and aging. In contrast, physical activity can increase mitochondrial biogenesis, improve ROS removal, and decrease apoptosis in skeletal muscle. Collectively, these studies suggest that mitochondrial content may be an important factor dictating cell function and survival. However, the direct effect of altered mitochondrial content on oxidative stress and apoptosis has not been studied in any cell type including skeletal muscle. The proposed research will alter mitochondrial content in vitro (in muscle and non-muscle cells) and in vivo (skeletal muscle) using several different approaches. Using state-of-the-art methods, we will comprehensively examine how apoptosis and oxidative stress (at a basal state and in response to cellular stress) are altered in conditions of low or high mitochondrial content. Further, the efficacy of regular physical activity (which induces mitochondrial biogenesis in muscle) will be evaluated as a strategy to inhibit skeletal muscle oxidative stress, apoptosis, and atrophy in response to chemical stress and a pathophysiological condition of muscle atrophy. Ultimately, the findings of this research could have important implications for understanding the molecular mechanisms that regulate skeletal muscle apoptosis and physiological adaptations that occur with exercise.