The mitochondrial permeability transition pore in muscle

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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.