The reciprocal regulation between mitochondrial-associated membranes and Notch signaling in skeletal muscle atrophy

Skeletal muscle atrophy and the inhibition of muscle regeneration are known to occur as a natural consequence of aging, yet the underlying mechanisms that lead to these processes in atrophic myofibers remain largely unclear. Our research has revealed that the maintenance of proper mitochondrial-associated endoplasmic reticulum membranes (MAM) is vital for preventing skeletal muscle atrophy in microgravity environments. We discovered that the deletion of the mitochondrial fusion protein Mitofusin2 (MFN2), which serves as a tether for MAM, in human iPS cells or the reduction of MAM in differentiated myotubes caused by microgravity interfered with myogenic differentiation process and an increased susceptibility to muscle atrophy, as well as the activation of the Notch signaling pathway. The atrophic phenotype of differentiated myotubes in microgravity and the regenerative capacity of Mfn2-deficient muscle stem cells in dystrophic mice were both ameliorated by treatment with the gamma-secretase inhibitor DAPT. Our findings demonstrate how the orchestration of mitochondrial morphology in differentiated myotubes and regenerating muscle stem cells plays a crucial role in regulating Notch signaling through the interaction of MAM. digestThis study investigated the link between Mfn2 and Notch signaling in skeletal muscle atrophy. We used a microgravity system to induce muscle atrophy and found that the loss of Mfn2 leads to decreased numbers of MAM and activation of Notch signaling and that treating MFN2-deficient human iPS cells with a gamma-secretase inhibitor DAPT improved their mitochondrial morphology and function. Additionally, Mfn2-deficient muscle stem cells in mice have a lower capacity to regenerate dystrophic muscles and DAPT treatment improves the regeneration of these cells. The study suggests that targeting the Notch signaling pathway with a gamma-secretase inhibitor could be a therapeutic option for skeletal muscle atrophy caused by defects in Mfn2.