Nitric Oxide Regulates Skeletal Muscle Fatigue, Fiber Type, Microtubule Organization, and Mitochondrial ATP Synthesis Efficiency Through cGMP-Dependent Mechanisms

Abstract

Aim: Skeletal muscle nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathways are impaired in Duchenne and Becker muscular dystrophy partly because of reduced nNOSl and soluble guanylate cyclase (GC) activity. However, GC function and the consequences of reduced GC activity in skeletal muscle are unknown. In this study, we explore the functions of GC and NO-cGMP signaling in skeletal muscle. Results: GC1, but not GC2, expression was higher in oxidative than glycolytic muscles. GC1 was found in a complex with nNOSl and targeted to nNOS compartments at the Golgi complex and neuromuscular junction. Baseline GC activity and GC agonist responsiveness was reduced in the absence of nNOS. Structural analyses revealed aberrant microtubule directionality in GC1 -/-muscle. Functional analyses of GC1 -/-muscles revealed reduced fatigue resistance and postexercise force recovery that were not due to shifts in type IIA-IIX fiber balance. Force deficits in GC1 -/-muscles were also not driven by defects in resting mitochondrial adenosine triphosphate (ATP) synthesis. However, increasing muscle cGMP with sildenafil decreased ATP synthesis efficiency and capacity, without impacting mitochondrial content or ultrastructure. Innovation: GC may represent a new target for alleviating muscle fatigue and that NO-cGMP signaling may play important roles in muscle structure, contractility, and bioenergetics. Conclusions: These findings suggest that GC activity is nNOS dependent and that muscle-specific control of GC expression and differential GC targeting may facilitate NO-cGMP signaling diversity. They suggest that nNOS regulates muscle fiber type, microtubule organization, fatigability, and postexercise force recovery partly through GC1 and suggest that NO-cGMP pathways may modulate mitochondrial ATP synthesis efficiency. Antioxid. Redox Signal. 26, 966-985.

Arginine promotes porcine type I muscle fibres formation through improvement of mitochondrial biogenesis

“…Arg is the unique natural precursor in the biosynthesis of NO by NOS (19) . A large number of studies showed that NO or NOS plays an important role in regulating muscle fibre type composition (20)(21)(22) . In the present study, we found that dietary supplementation of 1•0 % Arg increased NO content, NOS activity, protein expression of MyHC I and mRNA expressions of type I muscle fibres-related genes (MyHC I, Tnni1, Tnnc1 and Tnnt1) in longissimus dorsi muscle of weaning piglets.…”

Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth

“…Although, the initial animal studies of riociguat activity in adolescent rats and mice showed various degrees of bone resorption and remodeling in the femur and tibia [ 17 ], clinical studies in adults did not show any adverse effect on bones. In addition, we have reported normal bone densities in mice lacking GC1 demonstrating that GC1 does not play an important role in specifying bone density [ 66 ]. Regardless, the FDA has raised a concern for a future reference for use of riociguat in pediatric patients, even when conducting clinical trials [ 67 ].…”

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

“…Depending on tissue localization, NO regulation is different. For instance, in brown adipose or muscle tissue, several studies with eNOS knockout mice show that NO/cGMP pathway controls mitochondrial biogenesis [109,110]. However, in endothelial cells, NO is necessary to migration cells [111].…”