Skeletal Muscle as a Target for Cardio-Metabolic Disease in Sarcopenic Obesity

这个应用程序的目的是检查运动的副产品--肌肉质量如何增加 干预通常用于治疗肥胖和骨质疏松症，可以预防和挽救新陈代谢。 和血管功能障碍导致的骨质疏松症。这个应用程序的核心假设是靶向骨骼 衰老中的肌肉功能可以改善肥胖患者的代谢功能障碍和氧化剂诱导的高血压 并为建立一个独立的研究计划奠定基础，该计划旨在确定 肥胖所致的心脏代谢功能障碍可以通过随着年龄和特异性的增加而增加质量来挽救 纤维类型。 这项应用的目标将通过检查增加的肌肉质量的效果来实现，通过 肌肉抑制素缺失，对肥胖小鼠(db/db小鼠)心脏代谢功能的影响。实验 方法包括在清醒小鼠体内使用遥测血压，血管功能评估 使用分离血管的压力肌图，以及使用代谢室的代谢功能、葡萄糖 耐力测试，通过DXA Piximus对瘦体重和肥胖进行全身量化，以及血脂谱。 我们的数据表明，肥胖小鼠肌肉质量的增加可以防止肌肉质量的丧失和 力量、血糖控制和血管功能障碍，这些都伴随着db/db小鼠的肥胖。 重要的是，我们的初步数据表明，这些对代谢和心血管功能的改善 预防db/db小鼠高血压。此外，此应用程序将确定以下各项的相对贡献 器官特异性氧化应激，即血管NOX1和肾脏NOX4在肌源性肥胖模型中的作用。 目前使用的模型(结构性肌肉抑制素缺失)涉及终身增强肌。一个关键问题 仍未回答；是否可以增强肌肉救援/逆转肥胖引发的心血管功能障碍或IS 终身健身必不可少吗？申请人打算将他向独立的过渡集中在回答这些关键问题上 问题。我将在db/db小鼠中使用一种新的可诱导的myostatin基因敲除来确定是否增强 肌肉团块可以挽救完全肥胖表型发展后的代谢和血管功能障碍。 这将用于模拟患者群体，并允许将结果转化为临床。另外， 文献表明，骨骼肌纤维类型在预后中起着关键作用。使用的肌肉生长抑素模型 导致以糖酵解为主的骨骼肌扩张，如果确定 以氧化骨骼肌扩张为主的肥胖小鼠模型(Pgc1)也有类似的 改善心脏新陈代谢。

The objective of this application is to examine how augmented muscle mass, a by-product of the exercise intervention commonly prescribed for treatment of obesity and sarcopenia, can prevent and rescue metabolic and vascular dysfunction in sarcopenic obesity. The core hypothesis of this application is that targeting skeletal muscle function in aging can ameliorate metabolic dysfunction and oxidant-induced hypertension in obesity and lay the groundwork for establishment of an independent research program directed toward determining if obesity-derived cardiometabolic dysfunction can be rescued through augmented mass with aging and specific fiber types. The goals of this application will be accomplished by examining the effect of augmented muscle mass, through myostatin deletion, on cardiometabolic function in a mouse model of obesity (the db/db mouse). Experimental methods include in vivo blood pressure using telemetry in conscious mice, vascular function assessments using pressure myography of isolated vessels, and metabolic function using metabolic chambers, glucose tolerance tests, whole body quantification of lean mass and adiposity via DXA Piximus, and blood lipid profiles. Our data indicate that increasing muscle mass in obese mice protects against the loss of muscle mass and strength, glycemic control and vascular dysfunction, which accompany obesity in the db/db mouse. Importantly, our preliminary data indicate that these improvements to metabolic and cardiovascular function prevent hypertension in the db/db mouse. Further, this application will determine the relative contribution to organ specific oxidant stress, namely vascular NOX1 and renal NOX4 in a model of sarcopenic obesity. The model currently used (constitutive myostatin deletion) involves lifelong augmented muscle. A key question remains unanswered; can augmented muscle rescue/reverse obesity-derived cardiovascular dysfunction or is lifelong fitness essential? The applicant intends to focus his transition to independence on answering these key questions. I will use a novel inducible knockout of myostatin in a db/db mouse to determine if augmented muscle mass can rescue metabolic and vascular dysfunction after development of a fully obese phenotype. This will serve to mimic the patient population and allow for results to translate to the clinic. Additionally, literature suggests that skeletal muscle fiber type plays a crucial role in outcomes. The myostatin model used results in predominantly glycolytic skeletal muscle expansion and it would be advantageous to determine if a mouse model of obesity with predominantly oxidative skeletal muscle expansion (PGC1) would have similar cardiometabolic improvements.