The reciprocal regulation between mitochondrial-associated membranes and Notch signaling in skeletal muscle atrophy
Yurika Ito,
Mari Yamagata,
Takuya Yamamoto,
Katsuya Hirasaka,
Takeshi Nikawa,
Takahiko Sato
Affiliations
Yurika Ito
Faculty of Medical Sciences, Fujita Health University, Toyoake, Japan
Mari Yamagata
Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan
Takuya Yamamoto
Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan; Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan
Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Anatomy, Faculty of Medicine, Fujita Health University, Toyoake, Japan; International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan
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 induced pluripotent stem (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.
