Skeletal Muscle Basis for Improved Exercise Endurance in RGS14 KO

 描述(由申请人提供)：目前提交的是我们关于运动对G蛋白信号14受体(RGS14)敲除(KO)小鼠影响的修订申请。RGS14 KO模型展示了增强的运动耐量和能量利用，不仅导致长寿，更重要的是，健康衰老。RGS14 KO 减少β肾上腺素能受体信号，这可能与长寿一致，但作为改善运动的一种新颖和意想不到的机制，这是本应用的重点，因为增强的β肾上腺素能受体信号一直与改善运动能力有关。RGS14 KO模型具有增加棕色脂肪组织的额外的新颖、有益的属性，众所周知，它可以增加能量利用和预防糖尿病，但尚不清楚是否能调节增强的运动能力，这一点将在本应用中进行检验。RGS14 KO的另一个关键功能是它能够增加血管生成，这也将提高运动成绩，因为限制运动肌肉的血流会导致运动停止。目前应用的主要焦点是研究RGS14 KO模型中棕色脂肪组织和血管生成增强运动能力的生理和分子机制。这一点很重要，因为运动耐量降低对所有患有心血管疾病和其他疾病的患者来说都是关键，这会损害健康的生活方式和衰老，反过来，加强运动可以预防疾病，延长寿命。RGS14 KO还模仿了运动训练的有益功能。因此，开发一种可以给患者服用的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锻炼的负担。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.