Deficient nitric oxide signalling impairs skeletal muscle growth and performance: Involvement of mitochondrial dysregulation

Clara De Palma, Federica Morisi, Sarah Pambianco, Emma Assi, Thierry Touvier, Stefania Russo, Cristiana Perrotta, Vanina Romanello, Silvia Carnio, Valentina Cappello, Paolo Pellegrino, Claudia Moscheni, Maria Teresa Bassi, Marco Sandri, Davide Cervia, Emilio Clementi

Research output: Contribution to journalArticlepeer-review


Background: Nitric oxide (NO), generated in skeletal muscle mostly by the neuronal NO synthases (nNOSμ), has profound effects on both mitochondrial bioenergetics and muscle development and function. The importance of NO for muscle repair emerges from the observation that nNOS signalling is defective in many genetically diverse skeletal muscle diseases in which muscle repair is dysregulated. How the effects of NO/nNOSμ on mitochondria impact on muscle function, however, has not been investigated yet. Methods: In this study we have examined the relationship between the NO system, mitochondrial structure/activity and skeletal muscle phenotype/growth/functions using a mouse model in which nNOSμ is absent. Also, NO-induced effects and the NO pathway were dissected in myogenic precursor cells. Results: We show that nNOSμ deficiency in mouse skeletal muscle leads to altered mitochondrial bioenergetics and network remodelling, and increased mitochondrial unfolded protein response (UPRmt) and autophagy. The absence of nNOSμ is also accompanied by an altered mitochondrial homeostasis in myogenic precursor cells with a decrease in the number of myonuclei per fibre and impaired muscle development at early stages of perinatal growth. No alterations were observed, however, in the overall resting muscle structure, apart from a reduced specific muscle mass and cross sectional areas of the myofibres. Investigating the molecular mechanisms we found that nNOSμ deficiency was associated with an inhibition of the Akt-mammalian target of rapamycin pathway. Concomitantly, the Akt-FoxO3-mitochondrial E3 ubiquitin protein ligase 1 (Mul-1) axis was also dysregulated. In particular, inhibition of nNOS/NO/cyclic guanosine monophosphate (cGMP)/cGMP-dependent-protein kinases induced the transcriptional activity of FoxO3 and increased Mul-1 expression. nNOSμ deficiency was also accompanied by functional changes in muscle with reduced muscle force, decreased resistance to fatigue and increased degeneration/damage post-exercise. Conclusions: Our results indicate that nNOSμ/NO is required to regulate key homeostatic mechanisms in skeletal muscle, namely mitochondrial bioenergetics and network remodelling, UPRmt and autophagy. These events are likely associated with nNOSμ-dependent impairments of muscle fibre growth resulting in a deficit of muscle performance.

Original languageEnglish
Article number22
JournalSkeletal Muscle
Issue number1
Publication statusPublished - Dec 12 2014


  • Akt-FoxO3-Mul-1 axis
  • Akt-mTOR pathway
  • Autophagy
  • Fibre growth
  • Mitochondrial bioenergetics
  • Mitochondrial network
  • Muscle exercise
  • Muscle structure
  • Nitric oxide synthase and signalling
  • Unfolded protein response

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Orthopedics and Sports Medicine


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