nNOS regulation of skeletal muscle fatigue and exercise performance

Abstract

Neuronal nitric oxide synthases (nNOS) are Ca 2+ /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 Ca 2+ leak. This defect in Ca 2+ 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.

GSNOR Deficiency EnhancesIn SituSkeletal Muscle Strength, Fatigue Resistance, and RyR1 S-Nitrosylation Without Impacting Mitochondrial Content and Activity

“…These data suggest that NO can modulate muscle fatigue resistance through an Snitrosylation-/denitrosylation-dependent mechanism and that GSNOR acts as a brake on skeletal muscle force generation under physiological conditions. These data also support and extend previous studies, indicating an important role for NO synthesized by nNOS in skeletal muscle fatigue (1,19,46,48,49). Using a similar approach, nNOS deficiency (primarily the loss of nNOSb) substantially decreased both TA muscle fatigue resistance and postexercise force recovery (49).…”

“…Introduction N itric oxide (NO) plays many important roles in the skeletal muscle, where it is primarily synthesized by differentially localized nNOSl and nNOSb splice variants (38,46,49,58). NO from neuronal nitric oxide synthase (nNOS) has been implicated in the regulation of skeletal muscle oxidative-glycolytic fiber type balance, growth, atrophy, strength, fatigue resistance, local blood delivery and glucose uptake during contraction, insulin sensitivity, mitochondrial biogenesis, and mitochondrial activity (19,36,44,45,48,49,56,63,64).…”

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

“…However, subsequent studies by the same group made the opposite conclusion that NO in fact promotes muscle contractility under physiological conditions (20,32). This reevaluation agrees with the majority of subsequent studies, including the present one, which provides new evidence that NO-cGMP signaling does not inhibit muscle strength (54,56).…”

“…The second mechanism is the dynamic activity-dependent control of nNOSl localization (38,71). The third mechanism is differential nNOS isozyme sorting to create spatially and functionally distinct nNOS splice variant compartments at the sarcolemma, Golgi complex, neuromuscular junction, and sarcoplasmic reticulum (2,21,41,54,57,72). The fourth mechanism is the choice of target or effector for NO.…”

“…PDE5 catabolizes a small fraction of total cGMP in skeletal muscle and its functions in skeletal muscle cells are poorly defined (9). However, PDE5 does not appear to regulate skeletal muscle strength and fatigue resistance (54,60). In the dystrophin-deficient skeletal muscles of Duchenne and Becker muscular dystrophy (DBMD) patients and mdx mouse model of Duchenne muscular dystrophy (DMD), PDE5 plays clinically relevant roles in vasomodulation and fibrosis (6,40,47,50,55,60).…”