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: 7470590
• 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/7470590
• 关键词: Active Sites; Address; Affect; Age; Aging; Blood Circulation; Calpain; Caspase; Cells; Cysteine; Elderly; Elevation; Endopeptidases; 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; Other Finding; Pathway interactions; Peptide Hydrolases; Population; Process; Production; Proteins; Proteolysis; Proteolytic Processing; Quality of life; Rate; 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; human TNF protein; in vivo; insight; mouse model; multicatalytic endopeptidase complex; 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）：骨骼肌减少症，即在衰老过程中肌肉量的减少，是衰老不可避免的结果，对老年人的生活质量造成巨大影响，并使老年人容易受伤，从而进一步使人衰弱。肌肉减少症及其相关损伤和并发症的社会成本是巨大的，随着美国人口结构迅速向老年人口转变，这一成本将迅速增长。然而，缺乏关于肌肉减少症原因的机制知识阻碍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，衰老肌肉中的神经元一氧化氮合酶（nNOS）急剧减少，而将nNOS恢复到衰老肌肉中可以预防小鼠的肌肉减少症。我们这项研究的目的是确定nNOS预防肌肉减少症的机制。根据我们的初步研究和其他人的发现，我们提出了nnos衍生的NO通过两个过程减缓肌肉减少症的假设：1)抑制肌肉蛋白酶calpain-1， calpain-2和caspase-3，以减少肌纤维蛋白的蛋白质水解；2)抑制能够促进肌肉萎缩的炎症细胞因子的产生，特别是肿瘤坏死因子- α (TNFa)。我们将在衰老小鼠模型中通过测试no介导的s -亚硝基化是否在肌肉衰老过程中发生肌肉蛋白酶抑制来验证这一假设。钙蛋白酶抑制剂是否足以减少肌肉减少症将在经过基因改造的小鼠身上进行测试，这些小鼠在肌肉中产生高水平的钙蛋白酶抑制剂（钙pastatin）。我们还将确定由calpain-2或caspase-3引起的肌原纤维中主要肌肉蛋白的特异性蛋白水解修饰。在其他实验中，我们将测试操纵肌肉产生NO是否可以减少炎症细胞因子的产生，或炎症细胞对肌肉的侵袭。此外，我们将通过在干扰素- γ缺失小鼠上测试衰老是否会减少肌肉萎缩，从而确定减少促炎细胞因子的产生是否足以减缓肌肉减少症。我们期望这项研究的结果可以为减少肌肉减少症的潜在治疗策略提供新的见解。