Skeletal Muscle Basis for Improved Exercise Endurance in RGS14 KO

RGS14 KO 中提高运动耐力的骨骼肌基础

• 批准号: 9513046
• 负责人: STEPHEN F VATNER
• 金额: $ 50.08万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9513046
• 关键词: Age; Aging; Blood Circulation; Blood Vessels; Blood flow; Brown Fat; Cardiovascular system; Cause of Death; Diabetes Mellitus; Disease; Elderly; Energy Metabolism; Excision; Exercise; Exercise Tolerance; GTP-Binding Protein Regulators; GTP-Binding Proteins; Grant; Impairment; Individual; Knock-out; Knockout Mice; Life Style; Limb structure; Longevity; MEKs; Mediating; Mitochondria; Modeling; Molecular; Mus; Muscle; Muscle Fibers; Myocardial; Oxidative Stress; Pathway interactions; Patients; Performance; Peripheral; Physiological; Population; Public Health; Receptor Signaling; Regulation; Role; Signal Pathway; Signaling Protein; Skeletal Muscle; Therapeutic; Tissues; Translating; Transplantation; Vascular Endothelial Growth Factors; Work; angiogenesis; beta-adrenergic receptor; disability; endurance exercise; exercise capacity; exercise training; improved; inhibitor/antagonist; novel; public health relevance; receptor; small molecule inhibitor

 DESCRIPTION (provided by applicant): The current submission is a revised application for our grant on effects of exercise in the receptor of G protein signaling 14 (RGS14) knock out (KO) mouse. The RGS14 KO model, demonstrates enhanced exercise tolerance and energy utilization, resulting not only in longevity, but more significantly, healthful aging. The RGS14 KO reduces beta adrenergic receptor signaling, which might be consistent with longevity, but novel and unexpected as a mechanism for improved exercise, the focus of this application, since enhanced beta adrenergic receptor signaling has always been associated with improved exercise performance. The RGS14 KO model has the additional novel, salutary attribute of increased brown adipose tissue, which is known to increase energy utilization and protect against diabetes, but is not known to mediate enhanced exercise performance, which will be examined in this application. Another key feature of the RGS14 KO is its ability to increase angiogenesis, which would also enhance exercise performance, since limitation of blood flow to exercising muscle causes exercise to cease. The major focus of the current application is to examine the physiological and molecular mechanisms mediating the brown adipose tissue and angiogenesis induced enhanced exercise capacity in the RGS14 KO model. This is important because reduced exercise tolerance is central to all patients with cardiovascular and other diseases, impairing a healthy life style and aging, and conversely enhanced exercise protects against disease and extends longevity. The RGS14 KO also mimics the beneficial features of exercise training. Accordingly, developing an RGS14 inhibitor that can be given to patients would recapitulate the beneficial effects of exercise training without the burden placed on patients to undergo daily exercise. This last point is the focus of Aim C1 in this application.

 描述（由申请人提供）：当前提交的申请是我们对运动对 G 蛋白信号传导受体 14 (RGS14) 敲除 (KO) 小鼠的影响的修改申请，RGS14 KO 模型证明了运动耐力和能量的增强。 RGS14 KO 不仅可以延长寿命，更重要的是可以实现健康老龄化。 减少β肾上腺素能受体信号传导，这可能与长寿一致，但作为改善运动的机制新颖且出人意料，这是本申请的重点，因为增强的β肾上腺素能受体信号传导始终与改善的运动表现相关。棕色脂肪组织增加的另一个新颖、有益的属性已知可以增加能量利用率并预防糖尿病，但尚不清楚它是否可以介导增强运动表现，这将在本应用中进行研究。 KO 是其增加血管生成的能力，这也将增强运动表现，因为运动肌肉的血流限制会导致运动停止。当前应用的主要焦点是检查介导棕色脂肪组织和血管生成的生理和分子机制。在 RGS14 KO 模型中诱导运动能力增强这一点很重要，因为运动耐量降低对于所有患有心血管和其他疾病的患者至关重要，会损害健康的生活方式和衰老，相反，增强运动可以预防疾病并延长寿命。 RGS14 KO 还模仿了运动训练的有益特征，因此，开发一种可以给予患者的 RGS14 抑制剂将重现运动训练的有益效果，而不会给患者带来日常运动的负担。这最后一点是 Aim 的重点。本应用中的 C1。