Elevated Mitochondrial Ca2+ Impairs Satellite Cell Pool Expansion in Response to Skeletal Muscle Injury

Topic:

Pre-Clinical Research

Poster Number: 178 M

Author(s):

Ahmed Shams, MD/PhD, Greg Marzolf Jr. Muscular Dystrophy Center, Lillehei Heart Institute and Department of Pediatrics, M, Lalitha S. Denduluri, Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapol, Lauren LaScala, Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapol, Ingrid R. Aragon, Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapol, Jae Hwi Sung, Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapol, Sydney Peng, Greg Marzolf Jr. Muscular Dystrophy Center, Lillehei Heart Institute and Department of Pediatrics, M, Sarah J. Cornelius, Greg Marzolf Jr. Muscular Dystrophy Center, Lillehei Heart Institute and Department of Pediatrics, M, Sana Ikramuddin, Greg Marzolf Jr. Muscular Dystrophy Center, Lillehei Heart Institute and Department of Pediatrics, M, Aiden M. Boechler, Greg Marzolf Jr. Muscular Dystrophy Center, Lillehei Heart Institute and Department of Pediatrics, M, Eric Batchelor, Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapol, Michael Kyba, PhD, University of Minnesota, Julia C. Liu Liu, Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapol

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 one 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 cytosolic Ca2+ via the mitochondrial Ca2+ uniporter is integral to satellite cell activation from quiescence in response to muscle injury.