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。这一想法来自于一致的观察，即细胞死亡过程在各种肌肉萎缩条件下被激活，包括运动功能减退、卸载、去神经支配、营养不良、神经肌肉疾病和衰老诱导的肌肉减少症。了解这个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调查线粒体的作用，更具体地说，渗透性转换孔（PTP）在细胞死亡的激活。我们以前已经表明，线粒体从失神经肌肉变得脆弱的开放的PTP，一个重要的事件，在激活细胞死亡。此外，我们已经表明，线粒体对PTP开放的敏感性在肌肉类型中各不相同，这可能对理解肌肉如何应对废用具有重要意义。目前的建议旨在1）进一步建立PTP开放的脆弱性及其与去神经后细胞死亡的联系的机制，2）确定PTP在不太严重的废用模型中的参与，其中运动神经和肌肉之间的关系得到保留，3）确定负责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，这些信息将增强我们对肌纤维中PTP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带来新的见解，其中发生细胞死亡，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.