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

基本信息

批准号：
10623191
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
项目类别：
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/10623191
关键词：
Acceleration 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 Recommendation 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 absorption 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 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

项目摘要

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.

此应用程序的目的是检查运动副产品肌肉质量如何增加通常用于治疗肥胖和肌肉减少症的干预措施，可以预防和挽救代谢和肌肉减少性肥胖中的血管功能障碍该应用的核心假设是针对骨骼。衰老过程中的肌肉功能可以改善肥胖症中的代谢功能障碍和氧化诱发的高血压并为建立独立研究计划奠定基础，旨在确定是否肥胖引起的心脏代谢功能障碍可以通过随着年龄的增长和特定的体重增加而得到挽救纤维类型。该应用程序的目标将通过检查增强肌肉质量的效果来实现，通过肌生长抑制素缺失对肥胖小鼠模型（db/db 实验小鼠）心脏代谢功能的影响。方法包括使用遥测法对清醒小鼠进行体内血压测量、血管功能评估使用孤立血管的压力肌动描记法，以及使用代谢室、葡萄糖的代谢功能耐受性测试、通过 DXA Piximus 对瘦体重和肥胖进行全身量化以及血脂谱。我们的数据表明，增加肥胖小鼠的肌肉质量可以防止肌肉质量的损失和力量、血糖控制和血管功能障碍，这些都伴随着 db/db 小鼠的肥胖。重要的是，我们的初步数据表明，这些代谢和心血管功能的改善此外，该应用将确定对 db/db 小鼠的高血压的相对贡献。器官特异性氧化应激，即肌肉减少性肥胖模型中的血管 NOX1 和肾脏 NOX4。目前使用的模型（组成性肌生长抑制素缺失）涉及终生增强肌肉的一个关键问题。仍然没有答案；可以增强肌肉救援/逆转肥胖引起的心血管功能障碍吗？申请人打算将其过渡到独立的重点放在回答这些关键问题上吗？我将在 db/db 小鼠中使用新型诱导性敲除肌生长抑制素来确定是否增强。肌肉质量可以在完全肥胖表型发展后挽救代谢和血管功能障碍。这将有助于模仿患者群体并将结果转化为临床。文献表明骨骼肌纤维类型在使用的肌肉生长抑制素模型中起着至关重要的作用。导致主要是糖酵解骨骼肌扩张，并且确定是否是有利的以氧化骨骼肌扩张为主的肥胖小鼠模型 (PGC1) 也会有类似的结果心脏代谢改善。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The development of peripheral microvasculopathy with chronic metabolic disease in obese Zucker rats: a retrograde emergence?

肥胖 Zucker 大鼠周围微血管病变伴慢性代谢性疾病的发展：逆行出现？

DOI：
发表时间：
2022-09-01
期刊：
影响因子：
0
作者：
Halvorson, Brayden D;Menon, Nithin J;Goldman, Daniel;Frisbee, Stephanie J;Goodwill, Adam G;Butcher, Joshua T;Stapleton, Phoebe A;Brooks, Steven D;d'Audiffret, Alexandre C;Wiseman, Robert W;Lombard, Julian H;Brock, Robert W;Olfert, I Mark;Chan
通讯作者：
Chan

The biological clock enhancer nobiletin ameliorates steatosis in genetically obese mice by restoring aberrant hepatic circadian rhythm.

生物钟增强剂川陈皮素通过恢复异常的肝脏昼夜节律来改善遗传性肥胖小鼠的脂肪变性。

DOI：
发表时间：
2022-10-01
期刊：
影响因子：
0
作者：
Larion, Sebastian;Padgett, Caleb A;Butcher, Joshua T;Mintz, James D;Fulton, David J;Stepp, David W
通讯作者：
Stepp, David W

Changes in macrophage immunometabolism as a marker of skeletal muscle dysfunction across the lifespan.

巨噬细胞免疫代谢的变化作为整个生命周期骨骼肌功能障碍的标志。

DOI：
发表时间：
2023-05-25
期刊：
影响因子：
0
作者：
Liu, Norika;Butcher, Joshua T;Nakano, Atsushi;Del Campo, Andrea
通讯作者：
Del Campo, Andrea

Endothelial alpha globin is a nitrite reductase.

内皮α珠蛋白是一种亚硝酸还原酶。

DOI：
发表时间：
2022-10-27
期刊：
影响因子：
16.6
作者：
Keller 4th, T C Stevenson;Lechauve, Christophe;Keller, Alexander S;Broseghini;Butcher, Joshua T;Askew Page, Henry R;Islam, Aditi;Tan, Zhe Yin;DeLalio, Leon J;Brooks, Steven;Sharma, Poonam;Hong, Kwangseok;Xu, Wenhao;Padilha
通讯作者：
Padilha

Revisiting adipose thermogenesis for delaying aging and age-related diseases: Opportunities and challenges.

重新审视脂肪生热作用以延缓衰老和与年龄相关的疾病：机遇和挑战。

DOI：
发表时间：
2023-06
期刊：
影响因子：
13.1
作者：
Tarantini, Stefano;Subramanian, Madhan;Butcher, Joshua T;Yabluchanskiy, Andriy;Li, Xinna;Miller, Richard A;Balasubramanian, Priya
通讯作者：
Balasubramanian, Priya