Mitochondrial fission and remodelling contributes to muscle atrophy.
Mitochondria are crucial organelles in the production of energy and in the control of signalling cascades. A machinery of pro-fusion and fission proteins regulates their morphology and subcellular localization. In muscle this results in an orderly pattern of intermyofibrillar and subsarcolemmal mitochondria. Muscular atrophy is a genetically controlled process involving the activation of the autophagy-lysosome and the ubiquitin-proteasome systems. Whether and how the mitochondria are involved in muscular atrophy is unknown. Here, we show that the mitochondria are removed through autophagy system and that changes in mitochondrial network occur in atrophying muscles. Expression of the fission machinery is per se sufficient to cause muscle wasting in adult animals, by triggering organelle dysfunction and AMPK activation. Conversely, inhibition of the mitochondrial fission inhibits muscle loss during fasting and after FoxO3 overexpression. Mitochondrial-dependent muscle atrophy requires AMPK activation as inhibition of AMPK restores muscle size in myofibres with altered mitochondria. Thus, disruption of the mitochondrial network is an essential amplificatory loop of the muscular atrophy programme.
Romanello
Vanina
V
Dulbecco Telethon Institute at Venetian Institute of Molecular Medicine, Padova, Italy.
Guadagnin
Eleonora
E
Gomes
Ligia
L
Roder
Ira
I
Sandri
Claudia
C
Petersen
Yvonne
Y
Milan
Giulia
G
Masiero
Eva
E
Del Piccolo
Paola
P
Foretz
Marc
M
Scorrano
Luca
L
Rudolf
Rudiger
R
Sandri
Marco
M
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000473:pathology; D009133:Muscular Atrophy / Q000473:pathology*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
D055372:AMP-Activated Protein Kinases
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