Role of nitric oxide and reactive oxygen species in excitation-contraction coupling in skeletal muscle.

兴奋-收缩(E-C)偶联是一个广义的术语，用于描述一系列细胞事件，这些事件始于肌肉细胞表膜上的电信号，然后最终导致肌肉收缩。尽管整体序列已知，但我们对涉及的机制仍有许多空白，不仅与正常的肌肉功能有关，也与过度运动和疾病可能损害这一功能有关。许多细胞代谢物有助于肌肉收缩的正常控制，而其他代谢产物则有助于肌肉收缩的损害。活性氧簇(ROS)包括一氧化氮(NO)及其相关分子，是通常被称为细胞氧化剂的代谢因子。它们被认为在控制正常肌肉功能方面起着至关重要的作用。矛盾的是，它们还与疲劳、疾病和衰老相关的肌肉功能受损有关。这些分子如何既控制正常的肌肉活动，又导致这种功能的损害，目前尚不清楚。因此，该项目的中心目标是确定细胞氧化剂NO和其他ROS控制骨骼肌纤维中正常的E-C偶联的机制，以及它们如何导致肌肉疲劳。显然，为了更好地理解肌肉功能是如何随着运动、疾病和年龄而受损的，了解骨骼肌通常是如何收缩的是至关重要的。这项研究的工作将提供对正常肌肉生理学和肌肉如何疲劳的洞察，并最终提供可能对抗疲劳、疾病和年龄相关的肌肉功能变化的新方法和药物。

Excitation-contraction (E-C) coupling is a term used to broadly describe the sequence of cellular events that starts with an electrical signal at the surface membrane of a muscle cell and which then ultimately leads to muscle contraction. Although the overall sequence is known, there remain many gaps in our understanding of the mechanisms involved not only related to normal muscle function but to how this function may be impaired by excessive exercise and disease. Many cellular metabolites contribute towards the normal control of muscle contraction, while others contribute to its impairment. Reactive oxygen species (ROS), which includes nitric oxide (NO) and related molecules, are metabolic factors often referred to as cellular oxidants. They are thought to have an essential role in controlling normal muscle function. Paradoxically, they are also implicated in the impairment of muscle function associated with fatigue, disease and aging. How these molecules both control normal muscle activity and also contribute to impairment of such function remains unclear. Thus, the central aim of this project is to identify the mechanisms by which the cellular oxidants, NO and other ROS, both control normal E-C coupling in skeletal muscle fibres and how they contribute to muscle fatigue. Clearly, understanding how skeletal muscle normally contracts is essential in order to better understand how muscle function can become impaired with exercise, disease and age. The work from this study will provide insight into both normal muscle physiology and how muscles fatigue and ultimately provide new methodologies and drugs that may combat fatigue, disease and age related changes to muscle function.