Percival Justin M
Department of Physiology & Biophysics, University of Washington, Box 357290, Seattle, WA, 98195-7290, USA.
Biophys Rev. 2011 Dec;3(4):209-217. doi: 10.1007/s12551-011-0060-9. Epub 2011 Nov 8.
Neuronal nitric oxide synthases (nNOS) are Ca/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 leak. This defect in Ca 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.
神经元型一氧化氮合酶（nNOS）是钙/钙调蛋白激活的酶，可合成气态信使一氧化氮（NO）。nNOSμ和最近描述的nNOSβ均为剪接的nNOS同工型，是骨骼肌中NO的重要酶来源，骨骼肌长期以来被视为研究NO依赖性氧化还原信号传导的典型系统。nNOS对骨骼肌完整性和收缩性能不可或缺，nNOSμ信号失调是许多神经肌肉疾病的常见致病特征。最近的证据表明，nNOSμ和nNOSβ均调节骨骼肌大小、力量和抗疲劳能力，使其成为运动表现的重要参与者。nNOSμ充当活动传感器，似乎有助于骨骼肌适应新的功能需求，特别是耐力运动的需求。长期不活动会通过FoxO依赖性途径导致nNOS介导的肌肉萎缩。nNOS在调节神经肌肉疾病中的运动表现方面也发挥作用。在杜兴氏肌营养不良症的mdx小鼠模型中，nNOS信号缺陷被认为以两种方式限制工作肌肉的收缩能力：肌膜nNOSμ的丧失导致过度的缺血损伤，而残留的胞质nNOSμ导致兰尼碱受体的超硝化，导致致病性钙泄漏。这种钙处理缺陷会促进肌肉损伤、虚弱和疲劳。本综述阐述了在生理和神经肌肉疾病条件下，对nNOS依赖性骨骼肌功能和运动表现的氧化还原调节的这些最新进展。
