Exercise Response in Humans with Obesity

肥胖症患者的运动反应

• 批准号: 10659320
• 负责人: IAN R LANZA
• 金额: $ 71.29万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659320
• 关键词: Abdomen; Acute; Adipose tissue; Anatomy; Attenuated; Behavioral; Biochemical; Biology; Biopsy; Blood; Cells; Chemicals; Collection; Data; Disease; Endocrine; Event; Exercise; Exercise Physiology; Exhibits; Exposure to; Forskolin; Functional disorder; Gene Expression; Genes; Genetic; Human; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Ionomycin; Knowledge; Leg; Link; Macrophage; Measurement; Messenger RNA; Metabolic; Metabolic Diseases; Mission; Molecular; Muscle; Muscle Cells; Muscle Fibers; Muscle Proteins; Muscle function; National Institute of Diabetes and Digestive and Kidney Diseases; Obesity; Participant; Pathway interactions; Persons; Phenotype; Physiologic pulse; Population; Prevention; Protein Biosynthesis; Proteomics; Protocols documentation; Public Health; Research; Risk; Role; Signal Pathway; Signaling Protein; Skeletal Muscle; Stimulus; TLR4 gene; Testing; Thigh structure; Tissues; Tracer; Training; Work; cytokine; disability; experimental study; in vivo; in vivo imaging; insight; interdisciplinary approach; knock-down; mechanical stimulus; mitochondrial dysfunction; molecular phenotype; muscle physiology; non-invasive imaging; novel strategies; obese person; paracrine; pharmacologic; protein expression; resistance exercise; response; skeletal tissue; stable isotope; subcutaneous; tool; transcriptomics; translational study

Our preliminary data implicates inflamed adipose tissue as a factor that may lead to biochemical abnormalities in muscle and attenuate some of the adaptive responses to exercise in obese individuals. The objective of this project is to evaluate a hypothesis that adipose tissue inflammation activates inflammatory cascades in skeletal muscle that, in turn, attenuate molecular responses to exercise. Aim 1 will determine how adipose tissue phenotype influences skeletal muscle function and exercise response parameters in humans. Humans with obesity will complete studies to assess molecular response to acute exercise from protein synthesis rates, mRNA of exercise-responsive genes, and activation of signaling proteins in skeletal muscle. Subcutaneous adipose tissue (SAT) and intermuscular adipose tissue (IMAT) will be assessed using a combination of non-invasive imaging and biopsy-based molecular phenotyping. This aim will determine if acute exercise response is attenuated with increasing IMAT or in people with inflamed adipose tissue phenotype. Aim 2 will determine the mechanisms by which SAT and IMAT secretomes influence muscle phenotype and exercise response. Primary muscle cultures and adipose explants (SAT and IMAT) will be generated from participants in Aim 1. Myotubes will be exposed to conditioned media from IMAT, inflamed SAT, or non- inflamed SAT to evaluate their influence on molecular phenotype and exercise response pathways. Genetic and pharmacological approaches will be used to target key inflammatory pathways in skeletal muscle (TLR4, IKK, JAK/STAT) to assess their roles in exercise response in vitro. The contribution of the proposed research is expected to be a detailed understanding of the mechanistic links between adipose tissue inflammation, local inflammatory responses in skeletal muscle, and molecular response to acute exercise. The knowledge gained in the proposed study will have a positive impact because “exercise resistance” represents a significant barrier to the prevention and reversal of disease and disability in humans, and understanding the role of anatomically distinct adipose tissue pools in skeletal muscle physiology may lead to new approaches to enhance the beneficial adaptations to exercise in populations that stand to benefit most. Discovering new ways to enhance training responses in people, particularly those at risk for metabolic disorders, will have significant benefit since exercise non-responders have increased risk for metabolic disease.

我们的初步数据实现发炎的脂肪组织是可能导致生化异常的因素 在肌肉中，减轻了肥胖个体运动的一些适应性反应。这个目的 项目是评估一个假设，即脂肪组织注射激活骨骼中的炎症级联 肌肉反过来削弱了分子对运动的反应。 AIM 1将决定脂肪组织表型如何影响骨骼肌功能和运动 人类的响应参数。肥胖的人将完成研究以评估分子反应 从蛋白质合成速率，运动响应基因的mRNA和信号传导激活中进行急性运动 骨骼肌中的蛋白质。皮下脂肪组织（SAT）和肌间脂肪组织（IMAT）将 使用非侵入性成像和基于活检的分子表型的组合进行评估。这个目标 将确定急性运动反应是否随着IMAT的增加还是发炎的脂肪的人减弱 组织表型。 AIM 2将确定SAT和IMAT Secretomes影响肌肉表型的机制 和运动反应。将产生一级肌肉培养物和脂肪外植体（SAT和IMAT） 来自AIM 1的参与者。肌管将暴露于IMAT，发炎的SAT或非 - 发炎的SAT以评估其对分子表型和运动反应途径的影响。遗传 药物方法将用于靶向骨骼肌的关键炎症途径（TLR4， IKK，jak/stat）评估其在体外运动反应中的作用。 预计拟议研究的贡献将是对机械链接的详细理解 在脂肪组织感染，骨骼肌的局部炎症反应和分子之间 对急性运动的反应。拟议的研究中获得的知识将产生积极影响，因为 “运动抵抗”代表了预防和逆转疾病和残疾的重大障碍 人类，了解解剖上不同脂肪组织库在骨骼肌肉生理中的作用 可能会导致新的方法，以增强对人口中的锻炼的有益改编 受益最大。发现新的方法来增强人们的培训反应，尤其是那些有风险的人 代谢障碍，将有很大的好处 代谢疾病。