INRACELLULAR MILIEU AFFECTS MUSCLE CONTRACTION

细胞内环境影响肌肉收缩

• 批准号: 3352505
• 负责人: THOMAS M NOSEK
• 金额: $ 10.94万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-06-01 至 1990-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3352505
• 关键词: adenosine triphosphate; cellular pathology; heart failure; ion transport; ionic strengths; muscle contraction; phosphorylation; sarcoplasmic reticulum; smooth muscle; striated muscles

Muscle fatigue, defined as an inability to maintain a constant work intensity, has not been adequately explained on the cellular level. No matter how fatigue is produced (by extended repetition, ischemia, or hypoxia), it is accompanied by a qualitatively similar (though not identical) set of changes in the intracellular milieu. Our working hypothesis is that these changes in milieu are responsible for fatigue by causing major depressant effects on both the excitation-contraction coupling (ECC) process and the contractile apparatus (CA) of skeletal and cardiac muscle. Our work to date demonstrates that the net effect of milieu changes is to decrease the maximum force and calcium sensitivity of the CA. This net effect, the non-linear summation of the effects of changes in a number of intracellular constituents, does not totally explain the severe loss of force observed in intact, isolated muscles. The purpose of this proposal is to test the hypothesis in a two-fold manner: A) To complete the present series of experiments on skeletal and cardiac muscle: 1) by determining the dependence of the properties of the CA on free energy from ATP. 2) by determining whether the CA is sensitive to ionic strength or ionic equivalence as a measure of the intracellular ionic environment. B) To extend the scope of our studies to determine how the changes in milieu associated with fatigue affect. 1) the maximum velocity of shortening (Vmax - measured by the slack test). 2) the response to myosin light chain phosphorylation. 3) the ability of the sarcoplasmic reticulum (SR) to sequester and release calcium. 4) the ability of inositol trisphosphate (IP3), a possible second messenger, to modulate calcium-induced release of calcium from the SR. This project is unique in that it offers a unified and systematic approach to the problem of fatigue on the cellular level. Only such a study can: 1) determine the interactive effects of changing intracellular constituents (e.g. pH and Pi) to produce the net effect; 2) accurately compare properties of skeletal and cardiac fibers (e.g. the depressant effect of changes in phosphocreatine is greater in heart than in skeletal muscle). The proposed experiments will address both basic and clinical questions, the intrinsic mechanism of muscle contraction and the causes of its failure with fatigue.

肌肉疲劳，定义为无法保持恒定工作 强度在细胞水平上没有充分解释。 不 无论产生疲劳如何（通过扩展的重复，缺血或 缺氧），伴随着质量上的相似（尽管不是 相同的）细胞内环境的变化。 我们的工作 假设是，环境中的这些变化负责疲劳 对两种激发反应产生重大抑郁剂作用 耦合（ECC）过程和骨骼的收缩设备（CA）和 心肌。 迄今为止，我们的工作表明 环境的变化是降低最大力和钙灵敏度 大约 这种净效应，非线性的概括 许多细胞内成分的变化并不能完全解释 在完整的，孤立的肌肉中观察到的严重损失。 目的 该提议的内容是以两个方面的方式检验假设： a）完成有关骨骼和心脏的当前实验系列 肌肉： 1）通过确定CA的性质对自由能的依赖性 来自ATP。 2）确定CA是否对离子强度或离子敏感 等效性是对细胞内离子环境的量度。 b）扩展我们的研究范围以确定如何变化 与疲劳影响相关的环境。 1）缩短的最大速度（VMAX-通过松弛测试测量）。 2）对肌球蛋白轻链磷酸化的反应。 3）肌质网（SR）的能力隔离和释放 钙。 4）肌醇三磷酸（IP3）的能力，可能的第二 Messenger，以调节钙诱导的钙从SR中释放。 该项目的独特之处在于它提供了一种统一和系统的方法 在细胞水平上的疲劳问题。 只有这样的研究才能： 1）确定改变细胞内成分的互动效应 （例如pH和pi）产生净效应； 2）准确比较 骨骼纤维和心脏纤维的特性（例如 磷酸磷酸的变化比骨骼肌更大）。 拟议的实验将解决基本问题和临床问题， 肌肉收缩的内在机制及其失败的原因 有疲劳。