Institute for Transformative Molecular Medicine and Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16098-103. doi: 10.1073/pnas.1109546108. Epub 2011 Sep 6.
Physiological sensing of O(2) tension (partial O(2) pressure, pO(2)) plays an important role in some mammalian cellular systems, but striated muscle generally is not considered to be among them. Here we describe a molecular mechanism in skeletal muscle that acutely couples changes in pO(2) to altered calcium release through the ryanodine receptor-Ca(2+)-release channel (RyR1). Reactive oxygen species are generated in proportion to pO(2) by NADPH oxidase 4 (Nox4) in the sarcoplasmic reticulum, and the consequent oxidation of a small set of RyR1 cysteine thiols results in increased RyR1 activity and Ca(2+) release in isolated sarcoplasmic reticulum and in cultured myofibers and enhanced contractility of intact muscle. Thus, Nox4 is an O(2) sensor in skeletal muscle, and O(2)-coupled hydrogen peroxide production by Nox4 governs the redox state of regulatory RyR1 thiols and thereby governs muscle performance. These findings reveal a molecular mechanism for O(2)-based signaling by an NADPH oxidase and demonstrate a physiological role for oxidative modification of RyR1.
氧张力（部分氧分压，pO2）的生理感应在一些哺乳动物细胞系统中起着重要作用，但横纹肌通常不被认为属于其中之一。在这里，我们描述了一种在骨骼肌中的分子机制，该机制通过肌浆网中的烟酰胺腺嘌呤二核苷酸磷酸氧化酶 4（Nox4）将 pO2 的变化与钙释放的改变急性偶联，从而产生与 pO2 成比例的活性氧。肌浆网中的烟酰胺腺嘌呤二核苷酸磷酸氧化酶 4（Nox4）将 pO2 的变化与钙释放的改变急性偶联，从而产生与 pO2 成比例的活性氧。肌浆网中的烟酰胺腺嘌呤二核苷酸磷酸氧化酶 4（Nox4）将 pO2 的变化与钙释放的改变急性偶联，从而产生与 pO2 成比例的活性氧。肌浆网中的烟酰胺腺嘌呤二核苷酸磷酸氧化酶 4（Nox4）将 pO2 的变化与钙释放的改变急性偶联，从而产生与 pO2 成比例的活性氧。这些活性氧继而氧化一组小的肌浆网钙释放通道（RyR1）半胱氨酸硫醇，导致 RyR1 活性和钙释放增加，在分离的肌浆网和培养的肌纤维中增强收缩力，并增强完整肌肉的收缩性。因此，Nox4 是骨骼肌中的一种氧传感器，而 Nox4 产生的氧偶联过氧化氢通过调节 RyR1 硫醇的氧化还原状态来控制肌肉性能。这些发现揭示了 NADPH 氧化酶基于氧的信号转导的分子机制，并证明了 RyR1 氧化修饰的生理作用。
