ABSTRACT
Title
Nitric oxide and mitophagy are relevant for muscle regeneration capacity
Authors
S. Pisoni
Doctorate school in Medical Pharmacology, Chemioteraphy and Tossicology
Dept. of Clinical Science "Luigi Sacco", University of Milan, Italy
Doctorate school in Medical Pharmacology, Chemioteraphy and Tossicology
Dept. of Clinical Science "Luigi Sacco", University of Milan, Italy
Abstract
Autophagy, is a highly conserved mechanism carrying out degradation of cytoplasmic damaged organelles, toxin protein aggregates and intracellular pathogens. Plenty of evidence indicates that authophagy is important to maintain muscle mass and to prevent fibers degeneration1. Specific degradation of damaged mitochondria accounts for inhibition of apoptosis and muscle fibers survival; indeed mutations which inactivate Jumpy, a phosphatase that counteracts the activation of Beclin1/VPS34 and reduces autophagic flux, are associated with myofibers degeneration and development of centronuclear myopathy 2.
We showed that during myogenesis nitric oxide was a key factor involved in mitochondrial network formation and this allowed for the progression of correct myogenesis. In the absence of nitric oxide, mitochondria fragmented and depolarized, triggering the activation of autophagy. Autophagy was the mechanism adopted by myoblasts to protect themselves from apoptosis, indeed only in presence of 3-methyl-adenine we revealed apoptosis after mitochondrial fission. Furthermore we observed specific degradation of mitochondria, followed by LC3-II formation and specific activation of FoxO3 signaling pathway with an increase of nuclear FoxO3. Silencing FoxO3 myoblasts lost the protective mechanism displaying persistence of damaged mitochondria and evident signs of apoptosis. The same situation occurred in nNOS -/- mice; myoblasts differentiation was impaired and mitochondria were fragmented. Starvation-dependent autophagy was higher in these mice than in wt animals and we are currently establishing a clear correlation between mitophagy and muscle damage in this model. Definitely this work highlights the role of autophagy and of its link to the key molecule nitric oxide, in the context of muscle degeneration.
1 Masiero, E.et al. Autophagy is required to maintain muscle mass. Cell Metab 10, 507-515, (2009).
2 Vergne, I.et al. Control of autophagy initiation by phosphoinositide 3-phosphatase Jumpy. EMBO J 28, 2244-2258, (2009).
We showed that during myogenesis nitric oxide was a key factor involved in mitochondrial network formation and this allowed for the progression of correct myogenesis. In the absence of nitric oxide, mitochondria fragmented and depolarized, triggering the activation of autophagy. Autophagy was the mechanism adopted by myoblasts to protect themselves from apoptosis, indeed only in presence of 3-methyl-adenine we revealed apoptosis after mitochondrial fission. Furthermore we observed specific degradation of mitochondria, followed by LC3-II formation and specific activation of FoxO3 signaling pathway with an increase of nuclear FoxO3. Silencing FoxO3 myoblasts lost the protective mechanism displaying persistence of damaged mitochondria and evident signs of apoptosis. The same situation occurred in nNOS -/- mice; myoblasts differentiation was impaired and mitochondria were fragmented. Starvation-dependent autophagy was higher in these mice than in wt animals and we are currently establishing a clear correlation between mitophagy and muscle damage in this model. Definitely this work highlights the role of autophagy and of its link to the key molecule nitric oxide, in the context of muscle degeneration.
1 Masiero, E.et al. Autophagy is required to maintain muscle mass. Cell Metab 10, 507-515, (2009).
2 Vergne, I.et al. Control of autophagy initiation by phosphoinositide 3-phosphatase Jumpy. EMBO J 28, 2244-2258, (2009).