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.

我们的初步数据暗示发炎的脂肪组织作为一个因素，可能会导致生化异常 并减弱肥胖个体对运动的一些适应性反应。的目的 该项目旨在评估脂肪组织炎症激活骨骼肌炎症级联反应的假设， 肌肉，反过来，减弱分子对运动的反应。 目的1将确定脂肪组织表型如何影响骨骼肌功能和运动 人类的反应参数。肥胖症患者将完成评估分子反应的研究 蛋白质合成率、运动反应基因的mRNA和信号传导的激活 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。这一目标 将确定急性运动反应是否会随着IMAT的增加而减弱，或者在脂肪发炎的人中， 组织表型 目的2将确定SAT和IMAT分泌体影响肌肉表型的机制 运动反应。将生成原代肌肉培养物和脂肪外植体（SAT和IMAT） 目标1的参与者。肌管将暴露于来自IMAT、发炎SAT或非炎性SAT的条件培养基。 炎症SAT评估其对分子表型和运动反应途径的影响。遗传 和药理学方法将用于靶向骨骼肌中的关键炎症途径（TLR 4， IKK，JAK/STAT），以评估它们在体外运动反应中的作用。 所提出的研究的贡献预计将是一个详细的了解机制的联系 脂肪组织炎症，骨骼肌局部炎症反应， 对剧烈运动的反应。在拟议研究中获得的知识将产生积极影响，因为 “运动阻力”是预防和逆转疾病和残疾的一个重大障碍， 人类，并了解骨骼肌生理学中解剖学上不同的脂肪组织池的作用 可能会导致新的方法，以加强有益的适应运动的人群，站在 受益最多。发现新的方法来提高人们的训练反应，特别是那些有风险的人。 代谢紊乱，将有显着的好处，因为运动无反应者有增加的风险， 代谢性疾病