Regulation of sarcopenia and muscle dysfunction by nitric oxide

一氧化氮调节肌肉减少症和肌肉功能障碍

• 批准号: 7647903
• 负责人: JAMES G TIDBALL
• 金额: $ 32.45万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7647903
• 关键词: Active Sites; Address; Affect; Age; Aging; Blood Circulation; Calpain; Caspase; Cells; Cysteine; Elderly; Event; Functional disorder; Goals; Immunosuppressive Agents; Inflammatory; Injury; Interferon Type II; Interferons; Intervention; Investigation; Knockout Mice; Knowledge; Leukocytes; Mediating; Modification; Molecular; Mus; Muscle; Muscle Proteins; Myofibrils; Nitric Oxide; Nitric Oxide Synthase Type I; Pathway interactions; Peptide Hydrolases; Population; Process; Production; Proteins; Proteolysis; Proteolytic Processing; Quality of life; Regulation; Site; Skeletal Muscle; Testing; Therapeutic; Transgenes; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; United States; age related; aging population; base; calpain inhibitor; calpastatin; caspase-3; cost; cytokine; in vivo; insight; mouse model; multicatalytic endopeptidase complex; muscle aging; muscle form; mutant; prevent; research study; sarcopenia; senescence; wasting

DESCRIPTION (provided by applicant): Sarcopenia, the loss of muscle mass during aging, is an inevitable consequence of aging that takes a tremendous toll on the quality of life of the elderly, and predisposes the aging population to injuries that can be further debilitating. Societal cost of sarcopenia and associated injuries and complications is huge, and will grow rapidly as the United States demographic rapidly shifts toward a more senior population. However, the shortage of mechanistic knowledge concerning the causes of sarcopenia has prevented more specific interventions to slow the process of muscle wasting. Our findings show that aging muscle undergoes a dramatic reduction in neuronal nitric oxide synthase (nNOS) and that restoring nNOS to aging muscle prevents sarcopenia in mice. Our goal in this investigation is to identify the mechanisms through which nNOS protects against sarcopenia. Based upon our preliminary studies and the findings of others, we have generated the hypothesis that nNOS-derived NO slows sarcopenia through two processes: 1) inhibition of muscle proteases calpain-1, calpain-2 and caspase-3, to reduce proteolysis of myofibrillar proteins, and 2) inhibition in the production of inflammatory cytokines that are able to promote muscle wasting, especially tumor necrosis factor-alpha (TNFa). We will address this hypothesis in aging mouse models by testing whether muscle protease inhibition by NO-mediated S-nitrosylation occurs during muscle aging. Whether calpain inhibition is sufficient to reduce sarcopenia will be tested in mice that have been genetically-modified to produce elevated levels of the calpain inhibitor, calpastatin, in muscle. We will also identify the specific proteolytic modifications of major muscle proteins in myofibrils that are caused by calpain-2 or caspase-3. In other experiments, we will test whether manipulations of NO production by muscle can reduce the production of inflammatory cytokines, or muscle invasion by inflammatory cells. In addition, we will determine whether reducing the production of pro-inflammatory cytokines is sufficient to slow sarcopenia by testing whether muscle wasting is reduced in aging, TNFa null mutant on interferon-gamma null mice. We anticipate that the results of this investigation can provide new insights into potential therapeutic strategies to reduce sarcopenia.

描述（由申请人提供）：肌肉减少症，即衰老过程中肌肉质量的损失，是衰老的必然结果，对老年人的生活质量造成巨大损失，并使老年人群容易受到伤害，从而进一步使人衰弱。肌肉减少症和相关伤害和并发症的社会成本是巨大的，并且随着美国人口迅速向更高年龄人口转变，将迅速增长。然而，缺乏有关肌肉减少症原因的机械知识，阻止了更具体的干预措施来减缓肌肉萎缩的过程。我们的研究结果表明，衰老的肌肉经历了神经元型一氧化氮合酶（nNOS）的显着减少，并恢复nNOS老化肌肉防止小鼠肌肉减少症。我们在这项研究中的目标是确定nNOS保护肌肉减少症的机制。基于我们的初步研究和其他人的发现，我们已经产生了这样的假设，即nNOS衍生的NO通过两个过程减缓肌肉减少症：1）抑制肌肉蛋白酶钙蛋白酶-1、钙蛋白酶-2和半胱天冬酶-3，以减少肌原纤维蛋白的蛋白水解，和2）抑制能够促进肌肉萎缩的炎性细胞因子，特别是肿瘤坏死因子-α（TNF α）的产生。我们将在衰老小鼠模型中通过测试NO介导的S-亚硝基化是否会抑制肌肉蛋白酶来解决这一假设。钙蛋白酶抑制是否足以减少肌肉减少症将在已经被遗传修饰以在肌肉中产生升高水平的钙蛋白酶抑制剂钙蛋白酶抑制素的小鼠中进行测试。我们还将确定由钙蛋白酶-2或半胱天冬酶-3引起的肌原纤维中主要肌肉蛋白的特定蛋白水解修饰。在其他实验中，我们将测试是否操纵NO生产的肌肉可以减少炎症细胞因子的生产，或肌肉入侵的炎症细胞。此外，我们将通过测试在干扰素-γ缺失小鼠上的衰老、TNF α缺失突变体中肌肉萎缩是否减少来确定减少促炎细胞因子的产生是否足以减缓肌肉减少症。我们预计，这项调查的结果可以提供新的见解，潜在的治疗策略，以减少肌肉减少症。