Assessing and Alleviating Ca2+ Handling Dysfunction in Sarcopenia

评估和缓解肌少症患者的 Ca2 处理功能障碍

• 批准号: 9112384
• 负责人: MICHAEL C HOGAN
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112384
• 关键词: Affect; Age; Aging; Aging-Related Process; Antioxidants; Binding; Calcium; Cells; Contracts; Coupled; Dependence; Elderly; Elements; Environment; Exercise; Exercise Tolerance; Failure; Fatigue; Free Radicals; Functional disorder; Generations; Goals; Grant; HSP72 protein; Health; Homeostasis; Hormones; Human; Hypoxia; Imaging Techniques; Impairment; Inflammatory; Lead; Literature; Metabolic; Metabolism; Microfilaments; Mitochondria; Modeling; Modification; Monitor; Mus; Muscle; Muscle Fatigue; Muscle Fibers; Muscle function; Nitrates; Oxidative Stress; Oxygen; Pathway interactions; Performance; Physical Efforts; Physical activity; Physiological; Physiology; Process; Production; Property; Quality of life; Reactive Oxygen Species; Reporting; Research; Research Project Grants; Resistance; Respiration; Role; Ryanodine Receptors; Sarcoplasmic Reticulum; Series; Skeletal Muscle; Supplementation; Temperature; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Model; Uncertainty; Walking; Work; combat; cost; early onset; extracellular; frailty; improved; in vivo; juvenile animal; mitochondrial dysfunction; muscle aging; muscle form; muscle strength; normal aging; novel; overexpression; relating to nervous system; response; reuptake; sarcopenia; treatment strategy; wasting

 DESCRIPTION (provided by applicant): The progressive loss of skeletal muscle mass and strength, a condition known as sarcopenia, is perhaps the most debilitating age-associated alteration. In sarcopenia, muscle strength/power decrease significantly more than muscle mass itself, suggesting that it is the overall quality of the muscle that is affected and not only the sze or quantity of muscle. Muscle fatigue occurs when the intended physical activity can no longer be continued or is perceived as involving excessive effort. Unfortunately, many elderly suffer from fatigue at physical efforts far less (i.e. walking) than the efforts that are required to indue fatigue in healthy young people. Force generation in muscle is tightly coupled to the release and subsequent re-sequestering of Ca2+ by the sarcoplasmic reticulum (SR). Dysfunction in the Ca2+ handling process has been strongly implicated in the loss of force production in many fatigue producing situations, and it has been suggested that Ca2+ handling impairment may significantly contribute to skeletal muscle failure in sarcopenia. It is also known that tissue hypoxia is greater in aged muscle, and this may exacerbate the mechanisms contributing to Ca2+ handling failure. We have demonstrated that there is a range of reduced O2 availability that will induce "metabolic adaptation" to maintain mitochondrial respiration and energy generation (of which Ca2+ handling may require more than 40%!) such that lower intracellular O2 levels in aged muscle will result in a more perturbed intracellular milieu, resulting in an impaired muscle function--in part due to negative effects on the Ca2+ handling process. The interplay between O2 availability and Ca2+ handling on skeletal muscle dysfunction in the elderly has not been carefully investigated, and in particular, treatments for this impairment have not been analyzed. The purpose of this proposed research is to use mouse isolated whole muscle and an intact single skeletal muscle fiber model, in which the extracellular environment can be precisely controlled and the intracellular environment carefully monitored using non-invasive fluorescent imaging techniques, to: 1) test a number of hypotheses centered around the notion that cellular O2, at levels well above those limiting respiration, induce alterations in the intracellular environment that affect Ca2+ handling in aged muscle, thereby leading to an earlier onset of contractile impairment in hypoxia; and most importantly 2) test several novel compounds and transgenic models which affect different components of the Ca2+ handling process (release/myofilament binding/re- sequestration) in an attempt to develop therapeutic strategies for combating O2-related Ca2+ handling dysfunction and thereby alleviate some of the muscle impairment in sarcopenia. It is the goal of this research project to use our unique single myofiber model to carefully elucidate the mechanisms by which reduced cellular PO2 in aged muscle impairs Ca2+ handling and contractility, and to subsequently develop pharmacological strategies to reduce frailty associated Ca2+ handling impairments in older subjects.

 描述（由申请人提供）：骨骼肌质量和力量的逐渐丧失，称为肌肉减少症，可能是最令人衰弱的年龄相关变化。在肌肉减少症中，肌肉力量/力量的下降明显超过肌肉质量本身，这表明肌肉的整体质量受到影响，而不仅仅是肌肉的大小或数量。肌肉疲劳发生在预期的身体活动不能再继续或被认为涉及过度努力时。不幸的是，许多老年人在体力劳动（即步行）方面的疲劳远远低于健康年轻人引起疲劳所需的努力。肌肉中的力的产生与肌浆网（SR）释放和随后重新隔离Ca 2+紧密相关。Ca 2+处理过程中的功能障碍与许多疲劳产生情况下的力产生损失密切相关，并且已经表明Ca 2+处理损伤可能显著导致肌肉减少症中的骨骼肌衰竭。还已知组织缺氧在老化肌肉中更大，并且这可能加剧导致Ca 2+处理失败的机制。我们已经证明，有一系列减少的O2可用性，将诱导“代谢适应”，以维持线粒体呼吸和能量产生（其中Ca 2+处理可能需要超过40%！）这样，老化肌肉中较低的细胞内O2水平将导致更紊乱的细胞内环境，从而导致肌肉功能受损--部分原因是对Ca 2+处理过程的负面影响。老年人骨骼肌功能障碍的O2可用性和Ca 2+处理之间的相互作用尚未得到仔细研究，特别是，这种损伤的治疗方法 没有被分析。这项研究的目的是使用小鼠分离的整个肌肉和完整的单个骨骼肌纤维模型，其中细胞外环境可以精确控制，细胞内环境可以使用非侵入性荧光成像技术仔细监测，以：1）测试围绕细胞O2在远高于限制呼吸的水平时诱导细胞内环境改变的概念的许多假设。 细胞内环境影响老化肌肉中的Ca 2+处理，从而导致缺氧时收缩障碍的早期发作;最重要的是2）测试影响Ca 2+处理过程的不同组分的几种新化合物和转基因模型（释放/肌丝结合/再螯合），试图开发对抗O2相关的Ca 2+的治疗策略。处理功能障碍，从而减轻肌肉减少症中的一些肌肉损伤。本研究项目的目标是使用我们独特的单肌纤维模型来仔细阐明老年肌肉中细胞PO 2减少损害Ca 2+处理和收缩性的机制，并随后开发药理学策略来减少老年受试者中与脆弱相关的Ca 2+处理障碍。