Dysregulation of Mitochondrial Ca2+ Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1

摘要

Muscle function is regulated by Ca2+, which mediatesexcitation-contraction coupling, energy metabolism,adaptation to exercise, and sarcolemmalrepair. Several of these actions rely on Ca2+ deliveryto the mitochondrial matrix via the mitochondrialCa2+ uniporter, the pore of which is formed bymitochondrial calcium uniporter (MCU). MCU’s gatekeepingand cooperative activation are controlled byMICU1. Loss-of-protein mutation in MICU1 causes aneuromuscular disease. To determine the mechanismsunderlying the muscle impairments, we usedMICU1 patient cells and skeletal muscle-specificMICU1 knockout mice. Both these models show alower threshold for MCU-mediated Ca2+ uptake.Lack of MICU1 is associated with impaired mitochondrialCa2+ uptake during excitation-contraction,aerobic metabolism impairment, muscle weakness,fatigue, and myofiber damage during physical activity.MICU1 deficit compromises mitochondrial Ca2+uptake during sarcolemmal injury, which causes ineffectiverepair of the damaged myofibers. Thus, dysregulationof mitochondrial Ca2+ uptake hampersmyofiber contractile function, likely through energymetabolism and membrane repair.