Skeletal muscle sarcomere function in health and disease

骨骼肌肌节在健康和疾病中的功能

基本信息

批准号：
10655541
负责人：
JOSEPH Mark METZGER
金额：
$ 53.11万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
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/10655541
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 biophysical analysis effective therapy innovation mechanical load mechanotransduction myosin-binding protein C novel novel therapeutics prevent public health relevance restoration skeletal small molecule stem targeted treatment tool

项目摘要

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.

抽象的骨骼肌占体重的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，到坐着，站立和的基本日常运动步行，骨骼肌功能使人类状况充实。许多骨骼肌疾病引起明显的收缩功能障碍，导致整体健康和寿命大大降低在人类中。因此，防止或逆转肌肉功能障碍具有很大的健康相关性。这个建议重点关注肌膜 - 林木的功能单元 - 已知是多种形式的收缩的肌肉功能障碍。在杀虫剂肌病中，严重的肌肉无力是由低连接性肉瘤引起的，而远端关节炎的严重肌肉节期来自多动肉瘤。其他疾病，包括遗传性肌营养不良，也涉及改变肌节功能。这些疾病将肌节确定为治疗干预措施的关键但高度不足的靶标。骨骼肌涉及缺陷肉瘤的疾病无法治愈或有效治疗。进步的主要挑战集中于肌节调节的继承复杂性。最近，肌球蛋白杂交桥的小说已经提出了在机械感应调节控制下的激活状态，以与肌钙蛋白 - tropomyosin系统调节收缩。通过动态的胸膜间信号转导一起工作，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，数据支持该模型主要源自生物物理研究，物理相关性不清楚和关键阐明。我们开发并验证了一种基于FRET的新型肌节激活生物传感器集成到完整的骨骼肌的肌膜。初步数据显示生物传感器检测到构象肌钙蛋白的变化，用作实时报告载荷间丝间的信号联系在活骨骼肌中物理收缩期间肌膜激活的信号调节。指导假设：健康的骨骼肌功能需要通过动态实现的精确的肌节激活薄膜间信号传导，其中薄丝调节启动，肌球蛋白维持肌节激活在身体收缩期间；因此，有缺陷的胸膜间信号会导致疾病。目的正在研究在肌节激活中的胸膜间信号传导的物理机制在完整骨骼肌的抽搐收缩期间，并研究肌球蛋白结合蛋白C作为A 关键机理传感器管理层间信号传导过程，以调节肌节激活完整骨骼肌的抽搐收缩。阐明与物理相关的基本机制机械敏感的胸膜间信号传导将为推进新的基本框架在整个生命周期中保持健康的骨骼肌表现的治疗发现，并恢复正常遗传性肌病中的骨骼肌功能。