Dysregulation of Mitochondrial Ca ²⁺ Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1

SUMMARY

Muscle function is regulated by Ca ²⁺, which mediates excitation-contraction coupling, energy metabolism, adaptation to exercise, and sarcolemmal repair. Several of these actions rely on Ca ²⁺ delivery to the mitochondrial matrix via the mitochondrial Ca ²⁺ 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 Ca ²⁺ uptake. Lack of MICU1 is associated with impaired mitochondrial Ca ²⁺ uptake during excitation-contraction, aerobic metabolism impairment, muscle weakness, fatigue, and myofiber damage during physical activity. MICU1 deficit compromises mitochondrial Ca ²⁺ uptake during sarcolemmal injury, which causes ineffective repair of the damaged myofibers. Thus, dysregulation of mitochondrial Ca ²⁺ uptake hampers myofiber contractile function, likely through energy metabolism and membrane repair.

Graphical Abstract

In Brief

Debattisti et al. report that skeletal muscle-specific loss of mitochondrial Ca ²⁺ 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.