Cellular Mechanism for Sarcopenia in the Elderly

老年人肌肉减少症的细胞机制

• 批准号: 6328353
• 负责人: MARGARET A. MCNURLAN
• 金额: $ 44.03万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6328353
• 关键词: aging; biological signal transduction; biopsy; cytokine receptors; disease /disorder etiology; glucose transport; hormone sensitivity /resistance; human middle age (35-64); human old age (65+); human subject; inflammation; insulin; insulinlike growth factor; intracellular; muscle cells; muscle disorder chemotherapy; muscle metabolism; muscle proteins; patient oriented research; phenylalanine; phosphatidylinositol 3 kinase; photon absorptiometry; protein biosynthesis; sarcopenia; somatotropin; troglitazone; tumor necrosis factor alpha

Selective loss of muscle protein, or sarcopenia, is a significant problem for the elderly, leading to loss of muscle function and reducing the supply of amino acids that are available for mobilization in times of stress, which impacts on clinical outcome. Sarcopenia is undoubtedly multifactorial, including level of physical activity, and nutritional an l hormonal status, but this grant will focus on the contribution of inflammation on sarcopenia. At the tissue level, rates of muscle protein synthesis are reduced in the elderly, as they are in other conditions of injury or inflammation. This grant will investigate the role of inflammation on loss of muscle protein through diminished protein synthesis, and a reduced capacity of muscle protein synthesis to respond to the anabolic effects of hormones such as growth hormone (GH). Rates of muscle protein synthesis will be assessed from the incorporation of L- [2H5]phenylalanine into muscle protein, with distinction between myofibrillar (contractile) and sarcoplasmic (non-contractile) proteins. Rates of muscle protein synthesis will be correlated with markers of inflammation, including the soluble type 2 receptor for tumor necrosis factor (sTNFR-2). It is anticipated that individuals with inflammation will have reduced rates of muscle protein synthesis in the basal state and a diminished capacity to increase muscle protein synthesis in response to GH treatment. Rates of muscle protein synthesis will also be related to abnormalities at the cellular level, including changes in the intracellular signaling cascade for insulin and IGF-I through phosphatidylinositol 3-kinase (PI 3-K). This pathway is important in the regulation of both glucose transport and protein synthesis. Since insulin and insulin-like growth factor I share much of the same signaling cascade, diminished responsiveness of muscle protein synthesis to GH, in those individuals with higher levels of inflammation, should be apparent as a decrease in the intracellular signaling cascade through PI 3-K. Correlating cellular events with serum markers such as sTNFR-2 will provide a means of identifying individuals at risk of sarcopenia. Therapy with an insulin-sensitizing drug, thiazolidinedione, will be used to reduce the effects of TNFalpha on insulin signaling and to improve muscle protein synthesis.

对于老年人来说，选择性损失肌肉蛋白或肌肉减少症是一个重大问题，导致肌肉功能丧失，并减少在压力时可以动员的氨基酸的供应，这会影响临床结果。 肌肉减少症无疑是多因素的，包括体育锻炼水平和营养和荷尔蒙地位，但该赠款将集中于炎症对肌肉减少症的贡献。 在组织水平上，老年人的肌肉蛋白质合成率降低，就像其他损伤或炎症状况一样。 该赠款将通过减少蛋白质合成来研究炎症对肌肉蛋白质丧失的作用，以及肌肉蛋白合成的能力降低，以应对激素（如生长激素（GH））的合成代谢作用。 肌肉蛋白合成的速率将通过将L- [2H5]苯丙氨酸掺入肌肉蛋白中进行评估，并在肌原纤维（收缩）和肉质质（非合同）蛋白之间进行区别。 肌肉蛋白合成的速率将与炎症标志物相关，包括可溶性2型受体的肿瘤坏死因子（STNFR-2）。 预计炎症的个体将降低基底状态下肌肉蛋白质的合成率，并减少增加肌肉蛋白质合成的能力，以响应GH治疗。 肌肉蛋白合成的速率也将与细胞水平的异常有关，包括通过胰岛素和IGF-I通过磷脂酰氨基乙醇3-激酶（PI 3-K）的细胞内信号传导级联反应的变化。 该途径在调节葡萄糖转运和蛋白质合成方面很重要。 由于胰岛素和胰岛素样生长因子我具有相同的信号传导级联反应，因此在炎症较高水平的人中，肌肉蛋白质合成对GH的反应性降低，这是显而易见的，因为细胞内信号传导级联通过PI 3-K的降低。 将细胞事件与STNFR-2等血清标志物相关联，将提供一种识别有肌肉减少症风险的个体的方法。 用胰岛素敏化药物，噻唑烷二酮的治疗将用于减少tnfalpha对胰岛素信号传导的影响并改善肌肉蛋白质的合成。