Skeletal Muscle Basis for Improved Exercise Endurance in RGS14 KO

 描述（由申请人提供）：当前提交的是我们关于G蛋白信号传导受体14（RGS14）基因敲除（KO）小鼠运动效应的授权的修订申请。RGS14 KO模型证明了增强的运动耐力和能量利用，不仅导致长寿，而且更重要的是，健康的衰老。RGS14 KO 降低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是新颖的和出乎意料的，这是本申请的焦点，因为增强的β肾上腺素能受体信号传导总是与改善的运动表现相关。RGS14 KO模型具有增加的棕色脂肪组织的额外新颖有益属性，已知其增加能量利用并预防糖尿病，但不知道其介导增强的运动表现，这将在本申请中进行检查。RGS14 KO的另一个关键特征是其增加血管生成的能力，这也会增强运动表现，因为限制血流到运动肌肉会导致运动停止。本申请的主要焦点是在RGS14 KO模型中检查介导棕色脂肪组织和血管生成诱导的增强的运动能力的生理和分子机制。这一点很重要，因为运动耐量降低是所有心血管和其他疾病患者的核心，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功能。因此，开发一种可以给予患者的RGS14抑制剂将概括运动训练的有益效果，而不会给患者带来日常运动的负担。最后一点是本应用程序中目标C1的重点。

 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.