Abstract
During myogenic differentiation the short mitochondria of myoblasts change into the extensively elongated network observed in myotubes. The functional relevance and the molecular mechanisms driving the formation of this mitochondrial network are unknown. We now show that mitochondrial elongation is required for myogenesis to occur and that this event depends on the cellular generation of nitric oxide (NO). Inhibition of NO synthesis in myogenic precursor cells leads to inhibition of mitochondrial elongation and of myogenic differentiation. This is due to the enhanced activity, translocation and docking of the pro-fission GTPase dynamin-related protein-1 (Drp1) to mitochondria, leading also to a latent mitochondrial dysfunction that increased sensitivity to apoptotic stimuli. These effects of NO inhibition were not observed in myogenic precursor cells containing a dominant-negative form of Drp1. Both NO-dependent repression of Drp1 action and maintenance of mitochondrial integrity and function were mediated through the soluble guanylate cyclase. These data uncover a novel level of regulation of differentiation linking mitochondrial morphology and function to myogenic differentiation.
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Abbreviations
- NO:
-
nitric oxide
- Drp1:
-
dynamin-related protein-1
- Opa1:
-
optic atrophy-1
- NOS:
-
NO synthase
- cGMP:
-
cyclic GMP
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Acknowledgements
We thank Annie Higgs (London) for critically reading the paper, Erich Gnaiger (Innsbruck) for help with respirometry. This work was supported by Telethon Italia (GP007006, to EC), European Community 7th framework programme (OPTISTEM and ENDOSTEM large cooperative programmes, to EC and GC), Cariplo (to EC, MTB and SB), Associazione Italiana Ricerca sul Cancro (AIRC, to EC) Fondazione Romeo ed Enrica Invernizzi (to EC), Association Française contre Les Myopathies (AFM13478, to EC) and Italian Ministry of University (PRIN 2007, to EC). LS is a Senior Telethon Scientist of the Dulbecco-Telethon Institute and an EMBO Young Investigator. SC was a recipient of a fellowship from AIRC. CDeP, SF and SP performed the majority of the experiments and data analysis, and participated in project planning; SC and SP contributed to the bioenergetics experiments; CP prepared the various molecular biology tools; AD contributed to time-lapse microscopy; RA performed electron microscopy; MTB, GC, TP and L.S. performed some of the experiments and data analysis, and participated in project planning; LS, SM, SB and EC conceived the study, participated in project planning and wrote the paper.
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De Palma, C., Falcone, S., Pisoni, S. et al. Nitric oxide inhibition of Drp1-mediated mitochondrial fission is critical for myogenic differentiation. Cell Death Differ 17, 1684–1696 (2010). https://doi.org/10.1038/cdd.2010.48
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DOI: https://doi.org/10.1038/cdd.2010.48
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