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.

项目摘要 肥胖是心脏代谢疾病的主要驱动因素，也是美国死亡率的主要贡献者。一 其潜在机制是在高代谢器官如肝脏中异位脂质沉积增加， 骨骼肌（SKM），导致局部和最终全身代谢失调。肌脂肪变性定义为 由于脂肪渗透到骨骼肌中，其特征是肌肉质量的损失和 细胞内脂质这些外源性脂肪有助于升高的脂肪生成/脂肪分解状态， 脂质代谢物蓄积并损害胰岛素信号传导，促进全身胰岛素的形成 抵抗和最终的心脏代谢综合征（CMS）。众所周知，运动可以逆转胰岛素抵抗， 改善CMS独立的体重减轻，虽然机制仍然不完全理解。 此外，虽然运动的益处已被认识到，但患者的依从性和衰老阻碍了运动的效用， 提示需要药物干预。由于SKM是葡萄糖处置的主要场所， 和运动介导的适应最直接的效应，其生理变化提供了最 肥胖患者运动诱导心血管健康改善的明显机制。 来自该应用的初步数据确定，肥胖对新生儿的生长提供了有力的抑制。 血管在面对缺血，这是逆转与增加SKM质量由于删除的Mclinin 这表明我们先前研究的一个重要体内结果，显示了深刻的内皮细胞 功能障碍在新的数据中，我们表明从这些小鼠中分离的内皮细胞中的GAL 3和NOX 1表达， 是通过Mc的缺失来调节的，这表明它们也是血管生成受损的机制。的 GAL 3和NOX 1缺失对体内肥胖相关血管疾病的影响在很大程度上还未研究。在这 应用，我们将探讨肥胖驱动的异位脂肪堆积在SKM驱动血管的概念， 以GAL-3和NOX 1依赖性方式导致功能障碍和血管生成受损。这一目标将在两个 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识别潜在的机制 肥胖症中血管功能受损的驱动因素（GAL 3和NOX 1），已被确定为肥胖症患者的改善 肌肉发达的老鼠第二个将使用一种新的和新颖的基因敲除小鼠设计来解决脂肪变性 并测量心血管和代谢结果，以确定是否去除 异位脂肪可以作为一种可行的治疗方法。这个项目将在大卫博士的指导下进行 Stepp在奥古斯塔大学格鲁吉亚医学院血管生物学中心工作，该中心拥有丰富的 成功的博士前和博士后培训的历史。拟议项目为期3年，由 计划的目标分为3年的资金，在论文答辩结束时结束， 第三年。总之，成功完成这些目标将确定至少三个新的潜力， 肥胖相关的血管病变的治疗靶点，威胁外周血管。