The mitochondrial permeability transition pore in muscle

在过去的十年中，很明显，细胞死亡的激活在骨骼肌萎缩中起作用。这一观点来自于一致的观察，即细胞死亡过程在各种肌肉萎缩条件下被激活，包括运动障碍、卸载、神经支配丧失、营养不良、神经肌肉疾病和衰老引起的肌肉减少症。了解这一基本过程如何以及为什么在这些不同的情况下被激活是目前肌肉生理学/生物化学研究的一个重要领域。我们的研究计划旨在研究线粒体，更具体地说，是通透性过渡孔（PTP）在细胞死亡激活中的作用。我们之前已经表明，来自去神经支配肌肉的线粒体容易受到PTP打开的影响，这是细胞死亡激活的一个重要事件。此外，我们已经表明，线粒体对PTP打开的易感性因肌肉类型而异，这可能对理解肌肉如何对废用做出反应具有重要意义。目前的建议旨在1)进一步建立PTP开放脆弱性的机制及其与去神经支配后细胞死亡的联系，2)确定PTP在不太严重的失用模型中的参与，其中运动神经和肌肉之间的关系被保留，3)确定PTP的肌肉类型特异性调节的因素。这项工作将产生重要的新信息，将增强我们对肌纤维中PTP的调节及其在去神经萎缩后细胞死亡信号传导中的作用的理解。它还将为PTP参与其他形式的肌肉废用（其中发生细胞死亡）带来新的见解，包括肌肉不活动、正常衰老和神经肌肉疾病。

Over the last decade, it has become evident that activation of cell death play a role in skeletal muscle wasting. This idea has emerged from the consistent observation that cell death processes are activated under various muscle atrophic conditions including hypokinesia, unloading, denervation, dystrophy, neuromuscular disorders and aging-induced sarcopenia. Understanding how and why this fundamental process is activated under these various circumstances is currently an important area of research in muscle physiology/biochemistry. Our research program aims to investiguate the role of mitochondria, more specifically of the permeability transition pore (PTP) in the activation of cell death. We have previously shown that mitochondria from denervated muscle become vulnerable to opening of the PTP, an important event in the activation of cell death. Moreover, we have shown that the susceptibility of mitochondria to opening of the PTP varies across muscle types, which may have an importance in understanding how muscles will respond to disuse. The current proposal aims to 1) further establish the mechanisms underlying the vulnerability to PTP opening and its link with cell death following denervation, 2) determine the involvment of the PTP in less severe models of disuse in which the relationship between motor nerves and muscle is preserved and 3) identify the factors responsible for the muscle-type specific regulation of the PTP. This work will yield important new information that will enhance our understanding of the regulation of the PTP in muscle fibers, and its role in cell death signaling following denervation atrophy. It will also bring new insights on the involvement of the PTP in other forms of muscle disuse in which cell death occurs, including muscle inactivity, normal aging and neuromuscular disease.