The mitochondrial permeability transition pore in muscle

在过去的十年里，细胞死亡的激活在骨骼肌萎缩中起着重要作用，这一点已经变得明显。这一想法源于对细胞死亡过程的持续观察，即细胞死亡过程在各种肌肉萎缩条件下被激活，包括运动减退、卸载、失神经、营养不良、神经肌肉障碍和衰老引起的骨骼肌减少。了解这一基本过程是如何以及为什么在这些不同的环境下被激活的，是目前肌肉生理学/生化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，通透性转换孔(PTP)在激活细胞死亡中的作用。我们以前已经证明，失神经肌肉的线粒体对PTP的开放变得脆弱，PTP是细胞死亡激活中的一个重要事件。此外，我们已经表明，线粒体对PTP开放的敏感性因肌肉类型而异，这可能对了解肌肉对停用的反应有重要意义。目前的建议旨在1)进一步建立PTP开放的易损性及其与失神经后细胞死亡的联系的机制，2)确定在不太严重的废弃模型中PTP的参与，在该模型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，将加强我们对肌肉纤维中PTP的调节，以及它在失神经萎缩后细胞死亡信号中的作用的理解。它还将为PTP参与发生细胞死亡的其他形式的肌肉停用带来新的见解，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.