Grant: Travel Awards - Institute Community Support

Apoptosis, or cell death, has been frequently implicated in the age-related loss of muscle mass. A prominent role for mitochondrial dysfunction as a cause of this apoptosis has been proposed. The mitochondrial permeability transition pore (mtPTP) is a key channel involved in the regulation of mitochondrial-derived apoptosis initiating factors (AIF). Nuclear apoptosis occurs when these pro-apoptotic factors leave the mitochondria and locate to the nuclei, where they fragment DNA to initiate apoptosis. Previous studies have shown age-related increases in sensitivity to opening of the mPTP. To further investigate the relationship between mPTP dysfunction and mitochondrial-mediated apoptosis we have previously examined changes in mPTP function in four rodent muscles. These experiments showed that fast-twitch muscle exhibited a sensitization of the mPTP with aging, but no apparent change in in the slow twitch soleus muscle. However, these observations did not account for the influence of age-related shifts in the relative abundance of fast and slow fiber types. Overall, the purpose of these experiments is to determine if mPTP dysfunction contributes to age-related loss of muscle mass across different muscle types and if these changes are consistent with increased levels of AIF at the nuclei. To evaluate these hypotheses, we measured fiber type composition and nuclear-located AIF in 8 young adult and 10 very old rat muscles that have contrasting fiber type characteristics, but also markedly different changes in muscle mass with aging. We observed significant changes in fiber-type shifts, that when taken into account, reveal the mPTP as sensitized in all muscles that undergo atrophy. The nuclear AIF levels were elevated only in muscles undergoing atrophy with aging. As such, we have identified a common mechanism that drives atrophy of both fast and slow twitch muscles with aging, particularly in advanced age when the severity of atrophy is most clinically relevant