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

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Debattisti, Valentina 
Horn, Adam 
Singh, Raghavendra 
Seifert, Erin L 
Hogarth, Marshall W 


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.



atrophy, autosomal recessive, calcium, injury, membrane, mitochondria, mitochondrial disease, muscle disease, Adolescent, Adult, Animals, Calcium, Calcium Signaling, Calcium-Binding Proteins, Cation Transport Proteins, Cell Membrane, Cytosol, Female, Fibroblasts, Homeostasis, Humans, Male, Mice, Knockout, Mitochondria, Mitochondrial Membrane Transport Proteins, Models, Biological, Muscle Contraction, Muscle Weakness, Muscle, Skeletal, Muscular Atrophy, Sarcolemma, Tetanus, Wasting Syndrome

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Cell Rep

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Elsevier BV