Background: Nitric oxide (NO), generated in skeletal muscle mostly by the neuronal NO synthases (nNOS mu), 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/nNOS mu 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 nNOS mu is absent. Also, NO-induced effects and the NO pathway were dissected in myogenic precursor cells. Results: We show that nNOS mu 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 nNOS mu 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 nNOS mu 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. nNOS mu 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 nNOS mu/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 nNOS mu-dependent impairments of muscle fibre growth resulting in a deficit of muscle performance.
Deficient nitric oxide signalling impairs skeletal muscle growth and performance : involvement of mitochondrial dysregulation / C. De Palma, F. Morisi, S. Pambianco, E. Assi, T. Touvier, S. Russo, C. Perrotta, V. Romanello, S. Carnio, V. Cappello, P. Pellegrino, C. Moscheni, M.T. Bassi, M. Sandri, D. Cervia, E. Clementi. - In: SKELETAL MUSCLE. - ISSN 2044-5040. - 4(2014 Dec 12), pp. 22.1-22.21.
|Titolo:||Deficient nitric oxide signalling impairs skeletal muscle growth and performance : involvement of mitochondrial dysregulation|
DE PALMA, CLARA (Primo)
MORISI, FEDERICA (Secondo)
CLEMENTI, EMILIO GIUSEPPE IGNAZIO (Ultimo)
|Parole Chiave:||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|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||12-dic-2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1186/s13395-014-0022-6|
|Appare nelle tipologie:||01 - Articolo su periodico|