Role of Mitochondrial Calcium in the Maintenance of Skeletal Muscle Homeostasis

Abstract

PV is a member of the EF-hand Ca2+-binding family of proteins, expressed in fast-twitch muscle fibers where, acting as a soluble cytoplasmic Ca2+ buffer, contributes to musclerelaxation by removing Ca2+ from the cytosol and facilitating its transport back to the SR. Furthermore, PV is one of the most downregulated “atrogenes”, the family of genes commonly up- and downregulated in both systemic and disuse-induced muscle atrophy. We exploited the murine strain lacking PV (PV-/-) to explore the link between PV function as Ca2+ buffer and as determinant of muscle trophism. First, we confirmed that PV expression is downregulated in denervated muscles and, surprisingly, we found a trend to a lower muscle atrophy in PV-/- than in wild type (WT) mice. Then, by acutely silencing and overexpressing PV in adult muscles of WT mice, we discovered that downregulation was accompanied by hypertrophy and upregulation by atrophy. The lack of PV had a minor impact on sarcoplasmic reticulum and affected the kinetics but not the amplitude of the cytosolic Ca2+ transients. In contrast, PV ablation was associated with an increased Ca2+ uptake in mitochondria, partly supported by MCU increased expression and accompanied by increased mitochondria size and number. Intriguingly, MCU silencing abolished the hypertrophic effect of PV ablation, suggesting a mitochondrial Ca2+-dependent mechanism of control of muscle trophism. This was corroborated by the enhanced expression of the mitochondrial Ca2+-dependent PGC-1α4 that promotes skeletal muscle hypertrophy. MCU silencing prevented increase of PGC-1αα4 expression and PGC-1α4 silencing prevented muscle fiber hypertrophy. These data reveal a novel role of PV that links the control of cytosolic Ca2+ concentration to mitochondrial adaptations, ultimately leading to muscle mass regulation. We believe that our results further underline that the mitochondrial pathway and its regulation are of utmost importance to uncover the molecular mechanisms of muscle atrophy.