nNOS regulation of skeletal muscle fatigue and exercise performance

Abstract

Neuronal nitric oxide synthases (nNOS) are Ca²⁺/calmodulin-activated enzymes that synthesize the gaseous messenger nitric oxide (NO). nNOSμ and the recently described nNOSβ, both spliced nNOS isoforms, are important enzymatic sources of NO in skeletal muscle, a tissue long considered to be a paradigmatic system for studying NO-dependent redox signaling. nNOS is indispensable for skeletal muscle integrity and contractile performance, and deregulation of nNOSμ signaling is a common pathogenic feature of many neuromuscular diseases. Recent evidence suggests that both nNOSμ and nNOSβ regulate skeletal muscle size, strength, and fatigue resistance, making them important players in exercise performance. nNOSμ acts as an activity sensor and appears to assist skeletal muscle adaptation to new functional demands, particularly those of endurance exercise. Prolonged inactivity leads to nNOS-mediated muscle atrophy through a FoxO-dependent pathway. nNOS also plays a role in modulating exercise performance in neuromuscular disease. In the mdx mouse model of Duchenne muscular dystrophy, defective nNOS signaling is thought to restrict contractile capacity of working muscle in two ways: loss of sarcolemmal nNOSμ causes excessive ischemic damage while residual cytosolic nNOSμ contributes to hypernitrosylation of the ryanodine receptor, causing pathogenic Ca²⁺ leak. This defect in Ca²⁺ handling promotes muscle damage, weakness, and fatigue. This review addresses these recent advances in the understanding of nNOS-dependent redox regulation of skeletal muscle function and exercise performance under physiological and neuromuscular disease conditions.

Keywords: Dystrophin; Fatigue; Nitric oxide; Nitrosylation; Ryanodine receptor; nNOS.

Fig. 1

Model for the activity-dependent control of Ca²⁺/calmodulin (CaM) regulated neuronal nitric oxide synthase (nNOS) signaling and function. nNOSμ localizes to the dystrophin glycoprotein complex by binding a-syntrophin (a-syn), where it opposes blood vessel constriction during exercise. The spliced nNOS isoforms nNOSμ and nNOSβ (?) may regulate muscle fatigue and exercise performance by promoting normal ryanodine receptor 1 (RyR1) activity. SNO represents S-nitrosylation of regulatory cysteine thiols. RyR1 releases Ca²⁺ into the cytosol during contraction, while a sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) pumps Ca²⁺ from the cytosol back into the sarcoplasmic reticulum (SR). 1 nNOSμ signaling is increased by endurance type exercise. 2 Prolonged inactivity leads to dissociation of nNOSμ from the sarcolemma inducing atrophy through a forkhead transcription factor (FoxO) mediated pathway. 3 In Duchenne muscular dystrophy, loss of dystrophin destabilizes the dystrophin glycoprotein complex (DGC), and impairs the vasoregulatory function of nNOSμ, leading to RyR1 destabilization, pathogenic nNOSμ-mediated RyR1 hypernitrosylation and Ca²⁺ leak. 4 RyR1 Ca²⁺ leak can lead to muscle damage, weakness, and fatigue. RyR1 Ca²⁺ leak can further inappropriately activate nNOSμ, leading to further RyR1 nitrosylation and progressively more damaging Ca²⁺ leakage in a severely detrimental feed-forward loop