Mechanisms Controlling the Super-Relaxed State

控制超放松状态的机制

• 批准号: 8348651
• 负责人: EDWARD F PATE
• 金额: $ 50.42万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8348651
• 关键词: Affect; Agreement; Binding; Biological; Biology; Cardiac; Cardiac Myosins; Collaborations; Computer Simulation; Data; Development; Diabetes Mellitus; Disease; Electron Microscopy; Electron Spin Resonance Spectroscopy; Fatigue; Fiber; Filament; Fluorescence Spectroscopy; Goals; Head; Health; Heart; Heart Atrium; Human; Hypoxia; Imagery; Ischemia; Knowledge; Lead; Leg; Life; Measurement; Measures; Mechanics; Metabolic; Metabolism; Molecular Conformation; Monitor; Muscle; Muscle Fibers; Muscle Tension; Myocardium; Myosin ATPase; Myosin Light Chains; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Obesity; Phosphorylation; Physiological; Play; Population; Population Control; Population Decreases; Process; Property; Proteins; Protocols documentation; Reporting; Research; Rest; Role; Skeletal Muscle; Smooth Muscle; Stress; Structure; Temperature; Testing; Therapeutic Intervention; Thermodynamics; Thermogenesis; Thick Filament; Time; Variant; Ventricular; Work; analog; base; diabetes mellitus therapy; heart metabolism; skeletal

DESCRIPTION (provided by applicant): Our recent work has identified a new state of myosin in relaxed muscle with a very slow ATP turnover rate, the "super-relaxed state" (SRX). In skeletal muscle the SRX is proposed to play a role in determining thermogenesis by resting muscle. In cardiac ventricular muscle, where it has many similarities, but some important differences with the SRX in skeletal muscle, the SRX is proposed to play a cardio-protective role by efficiently de- creasing cardiac metabolism in times of stress. We have also shown that smooth muscle has a very stable SRX. Recent work has also demonstrated that in tarantula muscle the SRX has a very long duration, in agreement with previous EM data. The goal of the proposed research will be to determine the factors that modulate the SRX, particularly in skeletal, cardiac and smooth muscles. We have shown that the population of the SRX is modulated by RLC phosphorylation in fast skeletal muscle and in tarantula leg muscle. We will expand these studies to slow skeletal, cardiac and smooth muscles. Phosphorylation of myosin occurs in slow skeletal muscle; however its function remains unknown. The proposed research will explore a possible role in controlling the SRX and resting thermogenesis. In cardiac muscle, phosphorylation of myosin causes increased tension. Our recent work suggests that a role of the SRX in cardiac is to modulate tension, and we will explore the relationship between myosin phosphorylation, the population of the SRX and muscle tension. Observations in living, resting skeletal and cardiac muscle show that metabolism is dramatically decreased by fatigue and hypoxia. A high population of myosin in the SRX is a requirement for achieving the very low metabolic rate seen in resting skeletal muscle, and we propose also in cardiac. Thus we will explore the effect of conditions that mimic fatigue and hypoxia on the SRX. The studies will be extended to smooth muscle where phosphorylation also modulates function. These data will be complimented by structural studies of the SRX using EPR probes to monitor the structure of the thick filament and the conformation of the nucleotide pocket. Preliminary data suggest that nucleotide spin probes can report on the ordered structure of the thick filament. In collaboration with Roger Craig, spectroscopic probes will provide data that will be combined with EM visualization under identical conditions (phosphorylation, conditions of fatigue/hypoxia, etc.) to explore the structure of the SRX. These studies will vastly expand our very limited knowledge of this newly identified state of myosin. The studies will provide much of the fundamental biology whose understanding will be required to pursue our long-term goal, the development of the many obvious applications of the SRX for treating human health problems. Decreasing the population of the SRX in resting skeletal muscle could increase both muscle and whole body metabolism providing a new therapy for treating obesity and type 2 diabetes. Increasing the population of the SRX in resting and active cardiac muscle could lower the metabolic rate providing cardioprotection. PUBLIC HEALTH RELEVANCE: We have recently discovered a new state of myosin in resting muscle, which has a very low rate for using its fuel, ATP. We will investigate the biological mechanisms that control the population and other properties of this state. Understanding these mechanisms and how to manipulate them in skeletal muscle will lead to new therapies for diabetes and obesity, and in cardiac muscle to new therapies for protecting the heart in times of stress.

描述（由申请人提供）：我们最近的工作已经确定了肌球蛋白在放松肌肉中的一种新状态，具有非常缓慢的ATP周转率，即"超放松状态"（SRX）。在骨骼肌中，SRX被认为在确定静息肌肉产热中起作用。在心室肌中，它与骨骼肌中的SRX有许多相似之处，但也有一些重要的不同之处，SRX被认为通过在应激时有效地降低心脏代谢而发挥心脏保护作用。我们还发现平滑肌具有非常稳定的SRX。最近的工作也表明，在狼蛛肌肉的SRX有一个非常长的持续时间，与以前的EM数据。拟议研究的目标将是确定调节SRX的因素，特别是在骨骼肌、心肌和平滑肌中。我们已经表明，在快速骨骼肌和狼蛛腿肌的RLC磷酸化调制的SRX的人口。我们将把这些研究扩展到骨骼肌、心肌和平滑肌。肌球蛋白的磷酸化发生在慢速骨骼肌中，但其功能尚不清楚。这项研究将探索在控制SRX和静息产热中的可能作用。在心肌中，肌球蛋白的磷酸化导致张力增加。我们最近的工作表明，SRX在心脏中的作用是调节张力，我们将探讨肌球蛋白磷酸化，SRX的人口和肌肉张力之间的关系。对活的、静止的骨骼肌和心肌的观察表明，疲劳和缺氧会显著降低新陈代谢。在SRX中肌球蛋白的高群体是实现在静息骨骼肌中观察到的非常低的代谢率的要求，并且我们也建议在心脏中。因此，我们将探讨模拟疲劳和缺氧的条件对SRX的影响。这些研究将扩展到平滑肌，其中磷酸化也调节功能。这些数据将通过使用EPR探针对SRX的结构研究来补充，以监测粗丝的结构和核苷酸口袋的构象。初步数据表明，核苷酸自旋探针可以报告的粗丝的有序结构。与Roger克雷格合作，光谱探针将提供数据，这些数据将在相同条件下（磷酸化，疲劳/缺氧条件等）与EM可视化相结合。探索SRX的结构这些研究将极大地扩展我们对这种新发现的肌球蛋白状态的非常有限的知识。这些研究将提供大部分基础生物学知识，这些知识是追求我们的长期目标所需的，即开发SRX在治疗人类健康问题方面的许多明显应用。减少静息骨骼肌中SRX的数量可以增加肌肉和全身的代谢，为治疗肥胖和2型糖尿病提供了新的治疗方法。增加静息和活动心肌中SRX的数量可以降低代谢率，提供心脏保护。 公共卫生相关性：我们最近在静息肌肉中发现了一种新的肌球蛋白状态，这种肌球蛋白使用其燃料ATP的速率非常低。我们将研究控制这种状态的人口和其他属性的生物学机制。了解这些机制以及如何在骨骼肌中操纵它们将导致糖尿病和肥胖症的新疗法，以及在心肌中保护心脏的新疗法。