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Role of Mitochondrial Calcium in the Maintenance of Skeletal Muscle Homeostasis
Author(s) -
Raffaello Anna,
Vecellio Reane Denis,
Reggiani Carlo
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.00102
Subject(s) - downregulation and upregulation , gene silencing , mitochondrion , muscle hypertrophy , muscle atrophy , skeletal muscle , endoplasmic reticulum , microbiology and biotechnology , atrophy , endocrinology , biology , cytosol , medicine , chemistry , biochemistry , gene , enzyme
PV is a member of the EF‐hand Ca 2+ ‐binding family of proteins, expressed in fast‐twitch muscle fibers where, acting as a soluble cytoplasmic Ca 2+ buffer, contributes to musclerelaxation by removing Ca 2+ 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 Ca 2+ 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 Ca 2+ transients. In contrast, PV ablation was associated with an increased Ca 2+ 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 Ca 2+ ‐dependent mechanism of control of muscle trophism. This was corroborated by the enhanced expression of the mitochondrial Ca 2+ ‐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 Ca 2+ 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.