Skeletal muscle sarcomere function in health and disease

骨骼肌肌节在健康和疾病中的功能

• 批准号: 10445504
• 负责人: JOSEPH Mark METZGER
• 金额: $ 54.4万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445504
• 关键词: Address; Arthrogryposis; Biosensor; Breathing; Characteristics; Chemosensitization; Contractile Proteins; Contracture; Data; Disease; Distal; Fluorescence Resonance Energy Transfer; Functional disorder; Genetic; Health; Human; Hyperactivity; Inherited; Longevity; Memory; Microfilaments; Mission; Modeling; Molecular Conformation; Movement; Muscle; Muscle Weakness; Muscle function; Muscular Dystrophies; Myopathy; Myosin ATPase; Nemaline Myopathies; Performance; Personal Satisfaction; Pharmaceutical Preparations; Phosphorylation; Physiological; Process; Regulation; Reporting; Role; Sarcomeres; Signal Transduction; Skeletal Muscle; Stimulus; Striated Muscles; Structure; System; Testing; Therapeutic Intervention; Thin Filament; Time; Tropomyosin; Troponin; United States National Institutes of Health; Walking; base; biophysical analysis; effective therapy; innovation; mechanical load; mechanotransduction; myosin-binding protein C; novel; novel therapeutics; prevent; public health relevance; restoration; sensor; skeletal; small molecule; stem; targeted treatment; tool

Abstract Skeletal muscle accounts for 40% of body mass and defines in significant ways who we are as human beings. From the essential underpinnings of breathing, to the basic day-to-day movements of sitting, standing, and walking, skeletal muscle function enables the fullness of the human condition. Numerous skeletal muscle diseases cause marked contractile dysfunction leading to significantly diminished overall wellbeing and lifespan in humans. Therefore, preventing or reversing muscle dysfunction has significant health relevance. This proposal focuses on the sarcomere - the functional unit of striated muscle – known to underlie multiple forms of contractile dysfunction. In Nemaline myopathy, severe muscle weakness arises from hypoactive sarcomeres, while the severe muscle contractures characteristic of Distal Arthrogryposis stem from hyperactive sarcomeres. Other disorders, including inherited Muscular dystrophies, also involve altered sarcomere function. These diseases establish the sarcomere as a crucial, yet highly underserved, target for therapeutic intervention. Skeletal muscle diseases involving defective sarcomeres have no cure or effective treatments. A major challenge to progress centers on the inherent complexities of sarcomere regulation. Recently, novel ON/OFF myosin cross-bridge activation states under mechano-sensing regulatory control have been proposed to interface with the troponin- tropomyosin system to regulate contraction. Working together, through dynamic inter-myofilament signaling, this new view of sarcomere regulation has significant implications for muscle health and disease. To date, the data supporting this model derives mainly from biophysical studies, with physiological relevance unclear and critical to elucidate. We developed and validated a novel FRET-based sarcomere activation biosensor integrated into the myofilaments of intact skeletal muscle. Preliminary data shows the biosensor detects conformational changes in troponin, serving as a signaling nexus for real time reporting load-dependent inter-myofilament signaling regulation of sarcomere activation during physiological contractions in live skeletal muscles. Guiding hypothesis: Healthy skeletal muscle function requires precise sarcomere activation accomplished by dynamic inter-myofilament signaling wherein thin filament regulation initiates and myosin sustains sarcomere activation during physiological contraction; consequently, defective inter-myofilament signaling causes disease. The Aims are to investigate physiological mechanisms of inter-myofilament signaling in regulating sarcomere activation during twitch contractions in intact skeletal muscles and to investigate the effects myosin binding protein C as a key mechano-sensor governing inter-myofilament signaling processes in regulating sarcomere activation during twitch contractions in intact skeletal muscles. Elucidating the mechanisms underlying physiologically relevant mechano-sensitive inter-myofilament signaling will provide the essential framework for advancing new therapeutic discoveries to retain healthy skeletal muscle performance throughout lifespan, and to restore normal skeletal muscle function in inherited myopathies.

摘要 骨骼肌占身体质量的40%，并以重要的方式定义了我们作为人类的身份。 从呼吸的基本基础，到坐，站， 步行时，骨骼肌功能使人体状况更加充实。大量骨骼肌 疾病引起显著的收缩功能障碍，导致整体健康和寿命显著降低 在人类身上。因此，预防或逆转肌肉功能障碍具有显著的健康相关性。这项建议 肌节-横纹肌的功能单位-已知的基础多种形式的收缩 功能障碍在线状体肌病中，严重的肌无力源于肌节活动减退，而 远端关节挛缩的特征性严重肌肉挛缩源于过度活跃的肌节。其他 包括遗传性肌营养不良在内的疾病也涉及肌节功能的改变。这些疾病 建立肌节作为一个关键的，但高度不足，治疗干预的目标。骨骼肌 涉及有缺陷的肌节的疾病没有治愈或有效的治疗方法。对进步的重大挑战 集中于肌节调节的内在复杂性。最近，新型ON/OFF肌球蛋白跨桥 已经提出在机械感测调节控制下的激活状态与肌钙蛋白相互作用， 原肌球蛋白系统调节收缩。通过动态肌丝间信号传导， 肌节调节的新观点对肌肉健康和疾病具有重要意义。迄今为止，数据 支持这一模型的主要是生物物理学研究，其生理学相关性尚不清楚，也很关键 来阐明。我们开发并验证了一种新型的基于FRET的肌节激活生物传感器， 完整骨骼肌的肌丝初步数据显示，生物传感器检测构象 肌钙蛋白的变化，作为真实的时间报告负荷依赖性肌丝间的信号联系 在活骨骼肌的生理收缩期间肌节激活的信号调节。指导 假设：健康的骨骼肌功能需要精确的肌节激活， 肌丝间信号传导，其中细丝调节启动和肌球蛋白维持肌节激活 在生理收缩期间;因此，有缺陷的肌丝间信号传导导致疾病。目标 目的是研究肌丝间信号在调节肌节激活中的生理机制 在完整骨骼肌的抽搐收缩过程中，并研究肌球蛋白结合蛋白C作为一种 在调节肌节激活过程中控制肌丝间信号传导过程的关键机械传感器 完整骨骼肌的抽搐收缩。阐明生理相关的潜在机制 机械敏感的肌丝间信号传导将为推进新的 治疗发现，以保持健康的骨骼肌性能在整个生命周期，并恢复正常 遗传性肌病中的骨骼肌功能