Assessing and Alleviating Skeletal Muscle Ca2+ Handling Dysfunction in Sarcopenia

评估和缓解肌肉减少症患者的骨骼肌 Ca2 处理功能障碍

基本信息

批准号：
10083642
负责人：
MICHAEL C HOGAN
金额：
$ 33.08万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-10 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083642
关键词：
Acute Affect Age Aging Antioxidants Blood Vessels Calcium Cells Chronic Contracts Coupled Dependence Elderly Elements Environment Exercise Exercise Tolerance Experimental Models Failure Fatigue Free Radicals Functional disorder Generations Goals Grant 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 Muscular Atrophy Nitrates Oxygen Pathway interactions Performance Physical Efforts Physical activity Physiological Process Production Property Quality of life Reactive Oxygen Species Reporting Research Research Project Grants Resistance Respiration Rest Role Sarcoplasmic Reticulum Series Skeletal Muscle Supplementation Temperature Testing Therapeutic Tissues Transgenic Mice Transgenic Model Uncertainty Walking Work aged cost early onset extracellular fluorescence imaging frailty improved in vivo juvenile animal mitochondrial dysfunction muscle aging muscle form muscle physiology muscle strength normal aging overexpression preservation relating to nervous system response reuptake sarcopenia skeletal muscle wasting translational approach treatment strategy

项目摘要

PROJECT SUMMARY 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 size 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 induce 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%!). 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 to: 1) test a number of hypotheses centered around the notion that cellular O2 (at levels well above those limiting mitochondrial 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 treatments and transgenic models which affect different components of the Ca2+ handling process in an attempt to develop therapeutic strategies for combating O2-related Ca2+ handling dysfunction and thereby alleviate some of the muscle impairment in sarcopenia. Our experimental models allow precise control of the extracellular environment and the intracellular environment can be carefully monitored using non-invasive fluorescent imaging techniques. 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 strategies to reduce frailty associated Ca2+ handling impairments in older subjects.

项目摘要骨骼肌质量和力量的进行性丧失可能是一种称为肌肉减少症的疾病最衰弱的年龄相关的改变。在肌肉减少症中，肌肉力量/力量大大降低不仅仅是肌肉本身只有肌肉的大小或数量。肌肉疲劳发生在预期的体育锻炼不再继续或认为涉及付出的努力。不幸的是，许多较早的疲劳身体努力要比诱发健康年轻人疲劳所需的努力要少得多（即步行）人们。肌肉中的力产生与Ca2+的释放和随后再序列紧密耦合由肌质网（SR）。 CA2+处理过程中的功能障碍很强在许多疲劳生产情况下丧失力量生产的损失，已经是建议CA2+处理障碍可能会大大导致骨骼肌肉失败肌肉减少症。还知道组织缺氧在老年肌肉中更大，这可能会加剧导致CA2+处理故障的机制。我们已经证明了O2的范围还原可用性将引起“代谢适应”以保持线粒体呼吸和能量产生（其中CA2+处理可能需要超过40％！）。老年肌肉的细胞内O2水平将导致细胞内环境更加干扰，导致肌肉功能受损 - 部分是由于对CA2+处理过程的负面影响。 O2可用性与CA2+处理之间的相互作用古老的骨骼肌功能障碍尚未仔细研究，特别是这种障碍尚未分析。这项拟议的研究的目的是使用鼠标孤立的整个肌肉和完整的单个骨骼肌纤维至：1）测试许多假设集中在细胞O2的概念上（在限制线粒体的水平上呼吸）影响细胞内环境的改变，会影响老年人的Ca2+处理肌肉，从而导致缺氧的收缩障碍早期发作。最多重要的是：2）影响CA2+不同组成部分的测试处理和转基因模型处理过程试图制定理论策略来打击与O2相关的CA2+ 处理功能障碍，从而减轻肌肉减少症的某些肌肉障碍。我们的实验模型允许精确控制细胞外环境和细胞内环境可以使用非侵入性荧光成像技术仔细监测。这是这项研究的目标项目使用我们独特的单一肌纤维模型仔细阐明了减少的机制老年肌肉中的细胞PO2会损害CA2+处理和收缩力，然后制定策略减少老年受试者中脆弱的CA2+处理障碍。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of acute nitrite infusion on contractile economy and metabolism in isolated skeletal muscle in situ during hypoxia.

缺氧期间急性亚硝酸盐输注对原位离体骨骼肌收缩经济和代谢的影响。

DOI：
10.1113/jp279789
发表时间：
2020
期刊：
The Journal of physiology
影响因子：
0
作者：
Porcelli,Simone;Rasica,Letizia;Ferguson,BrianS;Kavazis,AndreasN;McDonald,James;Hogan,MichaelC;Grassi,Bruno;Gladden,LBruce
通讯作者：
Gladden,LBruce

Role of parvalbumin in fatigue-induced changes in force and cytosolic calcium transients in intact single mouse myofibers.

小清蛋白在疲劳引起的完整单只小鼠肌纤维中力和胞质钙瞬变变化中的作用。