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

• 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
• 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

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逐渐丧失，一种被称为肌肉减少症的疾病， 最令人衰弱的年龄相关的变化。在肌肉减少症中，肌肉力量/功率显著降低 比肌肉质量本身，这表明这是肌肉的整体质量受到影响，而不是 只有肌肉的大小或数量。肌肉疲劳发生时，预期的身体活动，不能再 继续或被认为涉及过度努力。不幸的是，许多老年人患有疲劳， 体力劳动（即步行）远远低于健康年轻人引起疲劳所需的努力 人肌肉中的力产生与Ca 2+的释放和随后的再隔离紧密耦合 肌浆网（SR）。钙处理过程中的功能障碍已经被强烈地 在许多疲劳产生的情况下，它与力产生的损失有关， 提示钙处理障碍可能显著导致骨骼肌衰竭， 肌肉减少症还已知的是，组织缺氧在老化的肌肉中更大，并且这可能加剧肌肉老化。 导致Ca 2+处理失败的机制。我们已经证明，有一个范围内的减少O2 这将诱导“代谢适应”，以维持线粒体呼吸和能量产生 (of其中Ca 2+处理可能需要超过40%！）。老化肌肉中较低的细胞内O2水平将 导致细胞内环境更加紊乱，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。O2可用性和Ca 2+处理之间的相互作用 老年人的骨骼肌功能障碍尚未得到仔细研究，特别是， 这一损害尚未得到分析。这项研究的目的是使用鼠标 分离的整个肌肉和完整的单个骨骼肌纤维，以：1）测试一些假设 围绕着这样一个概念，即细胞O2（水平远高于限制线粒体 呼吸）诱导细胞内环境的改变，影响老年人的Ca 2+处理。 肌肉，从而导致缺氧时收缩障碍的早期发作。和最 重要的是：2）影响Ca 2+不同组分的试验处理和转基因模型 处理过程，试图开发对抗O2相关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。我们 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。这是本研究的目标 项目使用我们独特的单肌纤维模型，仔细阐明减少肌纤维的机制。 老化肌肉中的细胞PO 2损害Ca 2+处理和收缩性，并随后开发策略， 减少老年受试者中与虚弱相关的Ca 2+处理障碍。

项目成果

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
• 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。

• DOI: 10.1152/japplphysiol.00861.2021
• 发表时间: 2022
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Nogueira,Leonardo;Gilmore,NatalieK;Hogan,MichaelC
• 通讯作者: Hogan,MichaelC