De Palma 2014 Skelet Muscle

From Bioblast
Publications in the MiPMap
De Palma C, Morisi F, Pambianco S, Assi E, Touvier T, Russo S, Perrotta C, Romanello V, Carnio S, Cappello V, Pellegrino P, Moscheni C, Bassi MT, Sandri M, Cervia D, Clementi E (2014) Deficient nitric oxide signalling impairs skeletal muscle growth and performance: involvement of mitochondrial dysregulation. Skelet Muscle 4:22.

ยป PMID: 25530838

De Palma C, Morisi F, Pambianco S, Assi E, Touvier T, Russo S, Perrotta C, Romanello V, Carnio S, Cappello V, Pellegrino P, Moscheni C, Bassi MT, Sandri M, Cervia D, Clementi E (2014) Skelet Muscle

Abstract: Nitric oxide (NO), generated in skeletal muscle mostly by the neuronal NO synthases (nNOSฮผ), 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/nNOSฮผ on mitochondria impact on muscle function, however, has not been investigated yet.

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 nNOSฮผ is absent. Also, NO-induced effects and the NO pathway were dissected in myogenic precursor cells.

We show that nNOSฮผ deficiency in mouse skeletal muscle leads to altered mitochondrial bioenergetics and network remodelling, and increased mitochondrial unfolded protein response (UPR(mt)) and autophagy. The absence of nNOSฮผ 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 nNOSฮผ 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. nNOSฮผ deficiency was also accompanied by functional changes in muscle with reduced muscle force, decreased resistance to fatigue and increased degeneration/damage post-exercise.

Our results indicate that nNOSฮผ/NO is required to regulate key homeostatic mechanisms in skeletal muscle, namely mitochondrial bioenergetics and network remodelling, UPR(mt) and autophagy. These events are likely associated with nNOSฮผ-dependent impairments of muscle fibre growth resulting in a deficit of muscle performance. โ€ข Keywords: 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

โ€ข O2k-Network Lab: IT Milan Clementi E

Labels: MiParea: Respiration 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue, Isolated mitochondria 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, CIV, NS  HRR: Oxygraph-2k 

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