Exercise prevents early aging-induced impairments in relaxation and MERCs in skeletal muscle

Sarcopenia, or age-related muscle dysfunction, contributes to morbidity and mortality. Besides decreases in muscle force, sarcopenia is associated with atrophy and fast-to-slow fiber type switching, which is typically secondary to denervation in humans and rodents. However, very little is known about cellular changes preceding these important (mal)adaptations. It is well established that mitochondria and the sarcoplasmic reticulum are critical for tension generation in myofibers. They can physically interact to form subcellular hubs termed mitochondria-endo/sarcoplasmic reticulum contacts (MERCs). Whether changes to MERC structure or protein composition occur early in aging is unknown. Additionally, whether changes at MERCs may be related to alterations in contractile function remains to be studied. To address these, we studied three groups of male C57BL6N mice: healthy young adults (HYA, 5 mo. of age), early age-related muscle dysfunction (eAMD, 21 mo. of age) and another cohort of eAMD that underwent 6-8 weeks of treadmill training (eAMD+Ex). Compared to HYA, eAMD animals displayed preserved maximal force and minimal or no muscle atrophy. However, the eAMD group had ~20% lower rate of relaxation leading to ~40% greater fatigue vs. HYA (p <0.05). In saponin-permeabilized muscle fibers, mitochondrial oxidative capacity was unchanged in eAMD, yet H 2 O 2 emission nearly doubled (p<0.01). This trend was partially alleviated by aerobic exercise. Assessed via TEM, MERC length was decreased by 20% in eAMD animals, recovered in eAMD+Ex, and strongly correlated with relaxation rate across groups (r = 0.704, R 2 = 0.50, p <0.05). Proteomic analyses of muscle MAM fractions revealed 191 proteins modified by aging or exercise. Twenty-eight of these proteins were inversely modulated in these conditions, suggesting they may be particularly relevant to muscle health. Our results point to MERCs as molecular hubs modulating functional adaptions to regular exercise while also contributing to the onset of mitochondrial abnormalities and contractile dysfunction characteristic of sarcopenia. NIH (R56AG068320) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.