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

Muscle function is regulated by Ca2+, which mediates excitation-contraction coupling, energy metabolism, adaptation to exercise, and sarcolemmal repair. Several of these actions rely on Ca2+ delivery to the mitochondrial matrix via the mitochondrial Ca2+ uniporter, the pore of which is formed by mitochondrial calcium uniporter (MCU). MCU’s gatekeeping and cooperative activation are controlled by MICU1. Loss-of-protein mutation in MICU1 causes a neuromuscular disease. To determine the mechanisms underlying the muscle impairments, we used MICU1 patient cells and skeletal muscle-specific MICU1 knockout mice. Both these models show a lower threshold for MCU-mediated Ca2+ uptake. Lack of MICU1 is associated with impaired mitochondrial Ca2+ 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 ineffective repair of the damaged myofibers. Thus, dysregulation of mitochondrial Ca2+ uptake hampers myofiber contractile function, likely through energy metabolism and membrane repair. [Display omitted] •MICU1 is central to coupling MCU to skeletal muscle excitation and contraction•Muscle-specific lack of MICU1 in mouse recaps skeletal muscle symptoms in patients•Loss of the bioenergetic role of MICU1 contributes to muscle weakness and fatigue•Impaired membrane repair contributes to myofiber damage and high serum CK levels Debattisti et al. report that skeletal muscle-specific loss of mitochondrial Ca2+ uptake 1 (MICU1) in mouse impairs mitochondrial calcium signaling, energy metabolism, and membrane repair, leading to muscle weakness, fatigue, myofiber damage, and high CK levels, recapitulating the muscle symptoms of MICU1 loss in patients.