MOLECULAR SIGNALING IN MUSCULAR ADAPTION TO EXERCISE

肌肉运动适应中的分子信号传导

• 批准号: 2080709
• 负责人: WILLIAM E KRAUS
• 金额: $ 9.54万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2080709
• 关键词: adenylate cyclase; aldehyde lyase; biological signal transduction; calcium flux; cell differentiation; cyclic AMP; electrophysiology; exercise; gene expression; gene induction /repression; genetic library; genetic promoter element; genetic regulatory element; genetic transcription; innervation; laboratory rabbit; microinjections; mixed tissue /cell culture; molecular cloning; muscle cells; muscle contraction; muscle proteins; mutant; neural plasticity; striated muscles; transfection

The functional capacity of skeletal muscle is important for the performance of daily activities for all individuals: from the demanding training regimens of elite athletes, through routine activities of daily living for the healthy individual, to those of patients with the peripheral limitations of neurological and musculoskeletal diseases, as well as to those with coronary artery disease and congestive heart failure who are limited by central hemodynamic factors. After weeks of moderate to intense exercise training, the functional capacity of an individual to perform given tasks can be remarkably improved through a transformation of skeletal muscle that is mediated by alterations in the abundance of skeletal muscle proteins essential for excitation, contraction and energy metabolism. These changes in protein abundance are the consequence of exercise-induced changes in the transcriptional activity of nuclear and mitochondrial genes, implying that gene transcription is a target for signaling pathways that link contractile activity to changes in the phenotype of skeletal muscle. The overall goal is to address the question of how the skeletal myocyte senses a need to alter its molecular makeup to meet the external demands of tonic exercise, and responds to those demands chronically by altering gene expression for whole sets of genes in a programmed, orderly, but often divergent, manner. Early work has focused on the aldolase A gene, which is activated during myocyte differentiation, but whose activity is down-regulated in response to neural signals induced during tonic exercise. The protein products of this gene is among those that determine fiber phenotype and functional properties. We propose to extend these studies to address the following specific aims: 1) To clone the promoter of the rabbit skeletal muscle- specific aldolase A gene, followed by a detailed analysis, using transfection techniques, of the structure and function of the human aldolase A promoter in response to muscle-specific signals and signals for myocyte differentiation. 2) To determine the cis-elements that mediate transcriptional repression of this gene in response to increased contractile work in skeletal muscle by using direct DNA microinjection techniques and exercise conditioning. 3) To determine candidate proteins (third messengers or transcriptional effectors) that proximally regulate the aldolase A gene in response to increased contractile activity by analysis of cDNA subtraction libraries. 4) To further define the signaling pathways involved in transducing signals from the membrane to the nucleus in response to electrical depolarization, membrane deformation, calcium release and contraction. This will involve further study of the role of the adenylyl cyclase and cAMP in mediating regulation of the aldolase A gene during the phenotypic transformation of skeletal muscles during chronic exercise conditioning. Understanding the signaling pathways mediating the process of muscular adaption to increased contractile work may lead to better approaches for the treatment of patients with cardiovascular, musculoskeletal and neurological diseases.

骨骼肌的功能能力对于 所有个人日常活动的表现：从要求的 精英运动员的训练方案，通过日常活动 为健康者而活，为患者而活 神经系统和肌肉骨骼疾病的外周局限性，如 以及患有冠状动脉疾病和充血性心脏病的人 受中枢血流动力学因素限制的失败者。 几周后 中度到剧烈的运动训练，可以提高身体的功能能力 个人执行给定任务的能力可以通过 骨骼肌的转变是由改变介导的 丰富的兴奋所必需的骨骼肌蛋白， 收缩和能量代谢。 蛋白质丰度的这些变化 是运动引起的转录变化的结果 核和线粒体基因的活性，意味着该基因 转录是连接收缩的信号通路的目标 骨骼肌表型变化的活性。 整体 目标是解决骨骼肌细胞如何感知需求的问题 改变其分子组成以满足补品的外部需求 锻炼，并通过改变基因来长期响应这些需求 整套基因以程序化的、有序的方式表达，但通常 发散, 方式. 早期的工作集中在醛缩酶 A 基因上，该基因在 肌细胞分化，但其活性相应下调 强直运动期间诱发的神经信号。 蛋白质产品 该基因是决定纤维表型和功能的基因之一 特性。 我们建议扩展这些研究以解决以下问题 具体目标： 1）克隆兔骨骼肌启动子- 特定的醛缩酶 A 基因，然后进行详细分析，使用 转染技术，研究人类的结构和功能 醛缩酶A启动子响应肌肉特异性信号和信号 用于肌细胞分化。 2) 确定顺式元素 介导该基因的转录抑制，以响应增加的 使用直接 DNA 显微注射进行骨骼肌的收缩工作 技术和运动调节。 3) 确定候选蛋白 （第三信使或转录效应器）近端调节 醛缩酶 A 基因响应增加的收缩活性 cDNA消减文库的分析。 4) 进一步定义 信号通路涉及将信号从膜转导到 细胞核对电去极化的反应，膜 变形、钙释放和收缩。 这将进一步涉及 腺苷酸环化酶和cAMP在介导中的作用研究 表型转化过程中醛缩酶 A 基因的调控 慢性运动调节过程中骨骼肌的变化。 理解 介导肌肉适应过程的信号通路 增加收缩功可能会带来更好的方法 心血管、肌肉骨骼和疾病患者的治疗 神经系统疾病。