The Mitochondrial Calcium Uniporter Controls Skeletal Muscle Trophism In Vivo

Muscle atrophy contributes to the poor prognosis of many pathophysiological conditions, but pharmacological therapies are still limited. Muscle activity leads to major swings in mitochondrial [Ca2+], which control aerobic metabolism, cell death, and survival pathways. We investigated in vivo the effects of mitochondrial Ca2+ homeostasis in skeletal muscle function and trophism by overexpressing or silencing the mitochondrial calcium uniporter (MCU). The results demonstrate that in both developing and adult muscles, MCU-dependent mitochondrial Ca2+ uptake has a marked trophic effect that does not depend on aerobic control but impinges on two major hypertrophic pathways of skeletal muscle, PGC-1α4 and IGF1-Akt/PKB. In addition, MCU overexpression protects from denervation-induced atrophy. These data reveal a novel Ca2+-dependent organelle-to-nucleus signaling route that links mitochondrial function to the control of muscle mass and may represent a possible pharmacological target in conditions of muscle loss. [Display omitted] •MCU controls mitochondrial Ca2+ uptake in skeletal muscle in vivo•MCU is sufficient and required for muscle size control•Mitochondria control hypertrophy signaling pathways•MCU protects from denervation-induced atrophy Mammucari et al. show that mitochondrial Ca2+ uptake positively regulates skeletal muscle size in vivo. In particular, gain- and loss-of-function experiments demonstrate that modulation of the mitochondrial calcium uniporter (MCU) controls mitochondrial volume, hypertrophy signaling pathways, protein synthesis, and gene transcription. In addition, MCU overexpression counteracts denervation-induced atrophy.