Increasing muscle mass resolves vascular dysfunction in obesity

增加肌肉质量可以解决肥胖症的血管功能障碍

基本信息

批准号：
10679363
负责人：
Andrew Speese
金额：
$ 4.12万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679363
关键词：
Acute Aging American Angiopoietin-2 Aorta Automobile Driving Biology Blood Glucose Blood Vessels Blood flow Body Composition Body Weight decreased Cardiometabolic Disease Cardiovascular Diseases Cardiovascular system Cause of Death Cell Separation Chemistry Chronic Data Deposition Development Distal Down-Regulation Endothelial Cells Endothelium Enzymes Exercise Fatty acid glycerol esters Funding GDF8 gene Galectin 3 Gene Expression Genes Genetic Genetic Models Goals Health Hindlimb Impairment In Vitro Infiltration Insulin Resistance Intervention Intracellular Accumulation of Lipids Ischemia Knockout Mice Laboratories Link Lipids Liver Measurement Measures Mediating Mentorship Metabolic Metabolic syndrome Metabolism Modeling Mus Muscular Atrophy Myography NADPH Oxidase 1 Obese Mice Obesity Operative Surgical Procedures Organ Outcome Perfusion Peripheral Phenocopy Phenotype Physiological Physiology Plasma Recording of previous events Recovery Resolution Risk Risk Factors Role Site Skeletal Muscle Source Stearoyl-CoA Desaturase Syndrome Testing Therapeutic Training Triglycerides United States Universities VEGFA gene Vascular Diseases Western Blotting angiogenesis artery occlusion cardiometabolism cardiovascular health compliance behavior db/db mouse density design endothelial dysfunction femoral artery glucose disposal glucose tolerance glycation improved in vivo insight insulin sensitivity insulin signaling knockout gene mRNA Expression medical schools mortality mouse model muscle form muscle hypertrophy neovascularization new growth novel obese patients obese person overexpression oxidant stress pharmacologic post-doctoral training pre-doctoral preservation pressure protein expression receptor for advanced glycation endproducts response restraint sarcopenia skeletal muscle growth skeletal muscle wasting therapeutic target

项目摘要

PROJECT SUMMARY Obesity is a primary driver of cardiometabolic disease and a major contributor to American mortality. One potential mechanism of this is elevated ectopic lipid deposition in highly metabolic organs such as the liver and skeletal muscle (SKM) leading to local and eventually systemic metabolic dysregulation. Myosteatosis is defined as the infiltration of fat into skeletal muscle and is characterized by loss of muscle mass and accumulation of intracellular lipids. These exogenously sourced fats contribute to an elevated lipogenic/lipolytic state whereby lipid metabolites accumulate and impair insulin signaling, contributing to the development of systemic insulin resistance and eventually cardiometabolic syndrome (CMS). Exercise is known to reverse insulin resistance and ameliorate CMS independent of weight loss, though the mechanisms remain incompletely understood. Moreover, while benefits of exercise are recognized, patient compliance and aging impede exercise utility, suggesting the need for pharmacological interventions. Because SKM is the principal site of glucose disposal and the most immediate effector of exercise-mediated adaptation, changes in its physiology provide the most obvious mechanism for exercise-induced improvements to cardiovascular health seen in obese patients. Preliminary data from this application establishes that obesity provides potent restraint on the growth of new blood vessels in the face of ischemia, which is reversed with increased SKM mass due to deletion of MSTN in mice, suggesting an important in vivo consequence of our prior studies showing profound endothelial dysfunction. In novel data we show that GAL3 and NOX1 expression in endothelial cells isolated from these mice are regulated by deletion of MSTN, suggesting that they are also mechanisms of impaired angiogenesis. The impact of GAL3 and NOX1 deletion on obesity-related vascular diseases in vivo is largely unexplored. In this application, we will explore the concept that obesity-driven ectopic fat accumulation in SKM drives vascular dysfunction and impaired angiogenesis in a GAL-3 and NOX1 dependent manner. This goal will be met in two specific aims. The first will use novel models uniquely developed in our lab to identify potential mechanistic drivers (GAL3 and NOX1) of impaired vascular function in obesity that have been identified as improved in obese hypermuscular mice. The second will use a newly made and novel knockout mouse design to resolve steatosis in a genetic model of obesity and measure cardiovascular and metabolic outcomes to determine if removing ectopic fat could serve as a viable therapeutic. The project will be directed under the mentorship of Dr. David Stepp in the Vascular Biology Center at the Medical College of Georgia at Augusta University, which has a rich history of successful pre- and post-doctoral training. The proposed project is for 3 years of funding with the planned aims divided amongst the 3 years of funding, concluding with a dissertation defense at the end of the third year. Taken together, the successful completion of these aims will identify at least three new potential therapeutic targets in obesity-related vasculopathy that threaten the peripheral vasculature.

项目摘要肥胖是心脏代谢疾病的主要驱动力，也是美国死亡率的主要贡献者。一在高度代谢器官（例如肝脏）和骨骼肌（SKM）导致局部，最终系统性代谢失调。定义了Myosteatosis 随着脂肪浸润到骨骼肌中，其特征是肌肉质量损失和积累细胞内脂质。这些外源的脂肪有助于脂肪/脂溶性升高，从而脂质代谢产物积累并损害胰岛素信号传导，有助于全身胰岛素的发展电阻，最终是心脏代谢综合征（CMS）。已知运动可以逆转胰岛素抵抗和改善CMS独立于体重减轻，尽管这些机制仍未完全理解。此外，虽然认识到运动的益处，但患者遵守和衰老会阻碍运动实用程序，但提示需要药理干预措施。因为SKM是葡萄糖处置的主要部位运动介导的适应性最直接的效果因子，其生理学的变化提供了最大的作用肥胖患者看到的运动引起的心血管健康改善的明显机制。该应用程序的初步数据确定肥胖为新的增长提供了有效的限制面对缺血的血管，由于删除MSTN而导致SKM质量增加的血管小鼠，这表明我们先前研究表明内皮深处的体内结果重要功能障碍。在新的数据中，我们表明从这些小鼠分离的内皮细胞中的GAL3和NOX1表达由MSTN的缺失调节，表明它们也是血管生成受损的机制。这 GAL3和NOX1缺失对体内与肥胖相关的血管疾病的影响在很大程度上没有探索。在这个应用，我们将探讨以肥胖驱动的异位脂肪在SKM驱动血管中积累的概念 GAL-3和NOX1依赖性方式的功能障碍和血管生成受损。这个目标将两次实现具体目标。第一个将使用实验室中独特开发的新颖模型来识别潜在的机械肥胖症中血管功能受损的驱动因素（GAL3和NOX1）已被确定为肥胖的改善高肌肉小鼠。第二个将使用新型和新颖的淘汰鼠标设计来解决脂肪变性在肥胖的遗传模型并测量心血管和代谢结果以确定是否去除异位脂肪可以用作可行的治疗性。该项目将在大卫博士的指导下进行。奥古斯塔大学佐治亚大学医学院血管生物学中心的Stepp，该中心有丰富的成功的博士后培训的历史。拟议的项目与计划的目标分配在三年的资金中，以论文辩护在结束时进行了论文辩护。第三年。综上所述，这些目标的成功完成将至少确定三个新的潜力肥胖相关的血管病的治疗靶标，威胁到周围脉管系统。