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

• 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
• 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

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.

项目概要 肥胖是心脏代谢疾病的主要驱动因素，也是美国人死亡的主要原因。一 其潜在机制是肝脏等高代谢器官中异位脂质沉积增加 骨骼肌（SKM）导致局部乃至全身代谢失调。肌脂肪变性的定义 脂肪渗入骨骼肌，其特点是肌肉质量损失和脂肪积累 细胞内脂质。这些外源脂肪有助于提高脂肪生成/脂肪分解状态，从而 脂质代谢物积累并损害胰岛素信号传导，有助于全身胰岛素的发展 抵抗并最终导致心脏代谢综合征（CMS）。众所周知，运动可以逆转胰岛素抵抗， 改善 CMS 与减肥无关，但其机制仍不完全清楚。 此外，虽然锻炼的好处已得到认可，但患者的依从性和衰老阻碍了锻炼的效用， 表明需要药物干预。因为 SKM 是葡萄糖处理的主要场所 作为运动介导的适应的最直接效应器，其生理学的变化提供了最 在肥胖患者中观察到运动引起的心血管健康改善的明显机制。 该申请的初步数据表明，肥胖对新细胞的生长具有有效的抑制作用。 血管面临缺血，由于 MSTN 缺失，SKM 质量增加，缺血情况得以逆转。 小鼠，表明我们之前的研究显示了深刻的内皮细胞的重要体内结果 功能障碍。在新数据中，我们显示从这些小鼠中分离出的内皮细胞中 GAL3 和 NOX1 的表达 受到 MSTN 缺失的调节，表明它们也是血管生成受损的机制。这 GAL3 和 NOX1 缺失对体内肥胖相关血管疾病的影响很大程度上尚未被探索。在这个 应用中，我们将探讨肥胖驱动的 SKM 异位脂肪积累驱动血管的概念 以 GAL-3 和 NOX1 依赖性方式出现功能障碍和血管生成受损。这个目标将分两期实现 具体目标。第一个将使用我们实验室独特开发的新颖模型来识别潜在的机制 肥胖症中血管功能受损的驱动因素（GAL3 和 NOX1）已被确定在肥胖症中得到改善 肌肉发达的小鼠。第二个将使用新制作的新颖的敲除小鼠设计来解决脂肪变性 在肥胖的遗传模型中测量心血管和代谢结果以确定是否消除 异位脂肪可以作为一种可行的治疗方法。该项目将在大卫博士的指导下进行 Stepp 位于奥古斯塔大学佐治亚医学院血管生物学中心，该中心拥有丰富的 成功的博士前和博士后培训历史。拟议项目的资助期限为 3 年 计划目标分为 3 年资助，最后以论文答辩结束 第三年。总而言之，成功完成这些目标将确定至少三个新的潜力 威胁外周血管系统的肥胖相关血管病变的治疗目标。