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 [Ca(2+)], which control aerobic metabolism, cell death, and survival pathways. We investigated in vivo the effects of mitochondrial Ca(2+) 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 Ca(2+) 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 Ca(2+)-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.
Department of Biomedical Sciences, University of Padua, Padua 35131, Italy. Electronic address: cristina.mammucari@unipd.it.
Cristina
C
Mammucari
Department of Biomedical Sciences, University of Padua, Padua 35131, Italy.
Gaia
G
Gherardi
Department of Biomedical Sciences, University of Padua, Padua 35131, Italy.
Ilaria
I
Zamparo
Department of Biomedical Sciences, University of Padua, Padua 35131, Italy.
Anna
A
Raffaello
Ce.S.I. (Center for Research on Ageing) and D.N.I.C.S. (Department of Neuroscience, Imaging and Clinical Sciences), University "G. D'Annunzio" of Chieti, Chieti 66100, Italy.
Simona
S
Boncompagni
Department of Biology and CRIBI Biotechnology Center, University of Padua, Padua 35131, Italy.
Francesco
F
Chemello
Department of Biology and CRIBI Biotechnology Center, University of Padua, Padua 35131, Italy.
Stefano
S
Cagnin
Department of Biomedical Sciences, University of Padua, Padua 35131, Italy.
Alessandra
A
Braga
Department of Biomedical Sciences, University of Padua, Padua 35131, Italy.
Sofia
S
Zanin
Department of Biomedical Sciences, University of Padua, Padua 35131, Italy; Neuroscience Institute, National Research Council, Padua 35131, Italy.
Giorgia
G
Pallafacchina
International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste 34159, Italy.
Lorena
L
Zentilin
Department of Biomedical Sciences, University of Padua, Padua 35131, Italy; Neuroscience Institute, National Research Council, Padua 35131, Italy; Dulbecco Telethon Institute at Venetian Institute of Molecular Medicine, Padua 35129, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Naples 80131, Italy.
Marco
M
Sandri
Department of Biomedical Sciences, University of Padua, Padua 35131, Italy.
Diego
D
De Stefani
Ce.S.I. (Center for Research on Ageing) and D.N.I.C.S. (Department of Neuroscience, Imaging and Clinical Sciences), University "G. D'Annunzio" of Chieti, Chieti 66100, Italy.
Feliciano
F
Protasi
Department of Biology and CRIBI Biotechnology Center, University of Padua, Padua 35131, Italy.
Gerolamo
G
Lanfranchi
Department of Biomedical Sciences, University of Padua, Padua 35131, Italy; Neuroscience Institute, National Research Council, Padua 35131, Italy. Electronic address: rosario.rizzuto@unipd.it.
Rosario
R
Rizzuto
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism / Q000503:physiopathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D015220:Calcium Channels; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors; C519530:insulin-like growth factor-1, mouse; C034703:mitochondrial calcium uniporter; D002110:Caffeine; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium