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

骨骼肌作为肌肉减少性肥胖症心脏代谢疾病的靶标

• 批准号: 10221585
• 负责人: Joshua Thomas Butcher
• 金额: $ 12.88万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10221585
• 关键词: Adult; Age; Age-Months; Aging; Amino Acids; Animal Model; Biology; Blood; Blood Pressure; Blood Pressure Monitors; Blood Vessels; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Child; Clinic; Conscious; Data; Development; Disease; Dual-Energy X-Ray Absorptiometry; Elderly; Endothelium; Enterobacteria phage P1 Cre recombinase; Enzymes; Epidemic; Equilibrium; Evaluation; Exercise; Fiber; Functional disorder; GDF8 gene; Genes; Glucose; Glucose tolerance test; Goals; Growth; Hand; Health; Hypertension; Injury to Kidney; Intervention; Kidney; Knock-out; Life Style; Link; Literature; Locomotion; Medical; Metabolic; Metabolic dysfunction; Methods; Modeling; Mus; Muscle; Muscle Fibers; Muscle Proteins; Muscle function; Muscular Atrophy; Myography; NADPH Oxidase 1; Obese Mice; Obesity; Obesity Epidemic; Organ; Outcome; Oxidants; Pathology; Pathway interactions; Phenotype; Play; Population; Prevalence; Prevention; Production; Renal Hypertension; Renal function; Research; Risk Factors; Role; Skeletal Muscle; Stream; Superoxides; Telemetry; Testing; Therapeutic; Thinness; Tissues; Training; Transgenic Organisms; Translating; United States National Institutes of Health; Vascular Diseases; Work; aged; aging population; blood glucose regulation; blood lipid; blood pressure regulation; burden of illness; cardiometabolism; cytokine; db/db mouse; effective intervention; exercise intervention; experience; fitness; glycemic control; healthy aging; human model; impaired glucose tolerance; improved; improved outcome; in vivo; indexing; juvenile animal; kidney vascular structure; mouse model; muscle aging; muscle form; muscle strength; novel; obese patients; obesity treatment; overexpression; oxidant stress; patient population; pressure; prevent; programs; protein degradation; sarcopenia; sarcopenic obesity; skeletal muscle growth

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.

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.