Golgi and sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue and vasoconstriction in exercising mouse skeletal muscle
Golgi and sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue and vasoconstriction in exercising mouse skeletal muscle
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DOI：
10.1172/jci40736
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发表时间：
2010-03-01
影响因子：
15.9
通讯作者：
Froehner, Stanley C.
中科院分区：
文献类型：
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作者：
Percival, Justin M.;Anderson, Kendra N. E.;Froehner, Stanley C.
通过神经元型一氧化氮合酶(NNOS)剪接变异体nNOSu传递的信号对骨骼肌健康是必不可少的，在神经肌肉疾病中通常会减少。NNOSu被认为是骨骼肌中NO的主要来源。在这里，我们证明了一条我们认为是一条新的信号通路的存在，它由nNOS剪接变体nNOSβ介导，定位于小鼠骨骼肌细胞的高尔基复合体。与缺乏nNOSmU的肌肉相比，同时缺失nNOSmU和nNOSβ的肌肉是严重的肌病，表现为微管细胞骨架、高尔基复合体和线粒体的结构性缺陷。缺乏nNOSµ和nNOSβ的骨骼肌质量较小，本质上较弱，极易疲劳，并在运动后表现出明显的虚弱。我们的数据表明，nNOSβ是骨骼肌结构和功能完整性的关键调节因子，并证明了骨骼肌中存在两个不同的nNOS微域，这两个微域是由nNOS u定位于肌膜和nNOSβ定位于高尔基体而产生的。我们之前已经证明，肌膜nNOSu与活跃肌肉的新陈代谢需求相匹配。我们现在证明，nNOSβ同时调节骨骼肌在运动过程中和运动后维持力量产生的能力。因此，我们得出结论，nNOS剪接变异体是骨骼肌运动性能的关键调节因子。
Signaling via the neuronal NOS (nNOS) splice variant nNOS mu is essential for skeletal muscle health and is commonly reduced in neuromuscular disease. nNOS mu is thought to be the predominant source of NO in skeletal muscle. Here we demonstrate the existence of what we believe to be a novel signaling pathway, mediated by the nNOS splice variant nNOS beta, localized at the Golgi complex in mouse skeletal muscle cells. In contrast to muscles lacking nNOS mu alone, muscles missing both nNOS mu and nNOS beta were severely myopathic, exhibiting structural defects in the microtubule cytoskeleton, Golgi complex, and mitochondria. Skeletal muscles lacking both nNOS mu and nNOS beta were smaller in mass, intrinsically weak, highly susceptible to fatigue, and exhibited marked postexercise weakness. Our data indicate that nNOS beta is a critical regulator of the structural and functional integrity of skeletal muscle and demonstrate the existence of 2 functionally distinct nNOS micro-domains in skeletal muscle, created by the differential targeting of nNOS mu to the sarcolemma and nNOS beta to the Golgi. We have previously shown that sarcolemmal nNOS mu matches the blood supply to the metabolic demands of active muscle. We now demonstrate that nNOS beta simultaneously modulates the ability of skeletal muscle to maintain force production during and after exercise. We conclude therefore that nNOS splice variants are critical regulators of skeletal muscle exercise performance.