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.

项目总结 肥胖是心脏代谢性疾病的主要驱动力，也是美国人死亡的主要原因。一 其潜在机制是肝脏和肝脏等高代谢器官异位脂肪沉积增加。 骨骼肌(SKM)导致局部和最终全身代谢失调。肌瘤病的定义是 由于脂肪渗入骨骼肌，其特征是肌肉质量的丧失和 细胞内的脂质。这些来自外部的脂肪有助于提高产脂/解脂状态，从而 脂代谢产物积聚并损害胰岛素信号，促进全身性胰岛素的形成。 抵抗，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，并 改善不依赖于体重减轻的CMS，尽管其机制仍不完全清楚。 此外，虽然锻炼的好处得到了认可，但患者的顺从性和年龄阻碍了锻炼的效用， 这表明有必要进行药物干预。因为SKM是葡萄糖处置的主要部位 作为运动介导的适应的最直接效应者，其生理变化提供了最多 运动改善肥胖患者心血管健康的明显机制。 这项应用的初步数据表明，肥胖对新生婴儿的增长起到了强有力的抑制作用 缺血时的血管，由于MSTN的缺失，随着SKM质量的增加而逆转 小鼠，这表明我们之前的研究显示了深刻的内皮细胞，这是一个重要的体内结果 功能障碍。在新的数据中，我们发现Gal3和NOX1在从这些小鼠分离的内皮细胞中表达 受MSTN缺失的调控，提示它们也是血管生成受损的机制。这个 在体内，Gal3和NOX1缺失对肥胖相关血管疾病的影响在很大程度上尚不清楚。在这 应用，我们将探索肥胖驱动的SKM异位脂肪堆积驱动血管的概念 以GAL-3和NOX1依赖的方式出现功能障碍和血管生成障碍。这一目标将在两年内实现 明确的目标。第一个将使用我们实验室独特开发的新模型来确定潜在的机制 肥胖症血管功能受损的驱动因素(Gal3和NOX1)已被确认为肥胖症患者改善 肌肉发达的小鼠。第二个将使用一种新制造的新型基因敲除小鼠来解决脂肪变性 在肥胖的遗传模型中，并测量心血管和代谢结果，以确定 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。 奥古斯塔大学佐治亚州医学院血管生物学中心的Stepp博士说，该校拥有丰富的 成功的博士前和博士后培训的历史。拟议的项目为期3年，资金来自 计划的目标在三年的资助中分配，以论文答辩结束 第三年。总而言之，成功实现这些目标将确定至少三个新的潜力 肥胖相关血管病变威胁周围血管系统的治疗靶点。