Elevated mitochondrial Ca2+ impairs satellite cell pool expansion in response to skeletal muscle injury.

Abstract

MICU1 loss-of-function variants in human patients are associated with proximal muscle weakness and myopathy. Mitochondrial Ca²⁺ levels are basally elevated when MICU1, the gatekeeper of the mitochondrial Ca²⁺ uniporter, is absent. The importance of regulating mitochondrial Ca²⁺ in skeletal muscle has generally been studied in mature muscle fibers. How satellite cells are impacted by mitochondrial Ca²⁺ dysregulation is poorly understood. We investigated Micu1 deletion specifically in Pax7+ satellite cells to address this gap in knowledge. Colony-forming activity in vitro was unaffected in Micu1-deficient satellite cells, but colony sizes were smaller. Although satellite cell homeostasis was not significantly affected 1 month following Micu1 deletion, the regenerative response post-injury was significantly impaired. Satellite cell self-renewal from Micu1-deficient donor cells in transplant recipients was also heavily compromised. Our data suggest that properly gating mitochondrial Ca²⁺ import via the uniporter is integral to satellite cell activation from quiescence in response to muscle injury.