Skeletal muscle performance and cellular adaptations to high hemoglobin-oxygen affinity

骨骼肌性能和细胞对高血红蛋白-氧亲和力的适应

基本信息

批准号：
10292937
负责人：
Jonathon Senefeld
金额：
$ 5.22万
依托单位：
MAYO CLINIC ROCHESTER
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：
2020-08-26 至 2022-05-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10292937
关键词：
Acute Address Aerobic Affinity Altitude Anaerobic Bacteria Animal Model Area Binding Bioenergetics Biology Biopsy Blood Blood flow Blood gas Blood specimen Capnography Catheters Chronic Clinic Clinical Computer software Contracts Development Diffusion Disease Environment Exercise Extensor Extramural Activities Fatigue Femoral vein Fiber Fostering Funding Gases Goals Health Hemoglobin Human Hydrogen Hypoxia Imaging Techniques Intramuscular Isometric Contraction Kinetics Knee Knowledge Laboratory Research Lead Leg Long-Term Effects Lung Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Mentorship Metabolic Metabolism Mitochondria Molecular Muscle Muscle Fatigue Muscle Fibers Muscle Mitochondria Myosin ATPase Myosin Heavy Chains Nature Oxygen Patients Performance Perfusion Phosphorus Physiological Physiological Adaptation Physiology Radial Regulation Research Research Personnel Resolution Resources Role Sampling Silver Staining Skeletal Muscle Spin Labels Stains Technical Expertise Techniques Testing Tissues Training Transportation Variant Venous Work blood perfusion clinically relevant design exercise capacity experimental study innovation inorganic phosphate insight muscle physiology novel radial artery respiratory response skill acquisition

项目摘要

Project Summary/Abstract The overall goal of the proposed work is to investigate novel translational ideas about skeletal muscle performance in the context of the oxygen (O2) transport cascade during exercise in humans. The proposal is supported by an exceptional mentorship team and will provide the highly promising applicant significant support in his goal of becoming an independent investigator in translational integrative physiology. The specific aims leverage the applicant’s expertise in skeletal muscle physiology and the distinct expertise of the meritorious mentorship team on regulation of blood flow in humans (sponsor, Dr. Joyner), skeletal muscle and mitochondrial biology (co-sponsor, Dr. Lanza), skeletal muscle imaging techniques (collaborator, Dr. Port) and hemoglobin (Hb) variants (collaborators, Drs. Hoyer and Oliveira). Specific Aim 1 will test whether high Hb- O2 affinity will exacerbate skeletal muscle fatigue and reduce skeletal muscle O2 extraction during fatiguing exercise. We will assess fatigue of the knee extensor muscles during a sustained, 60-s maximal voluntary isometric contraction and we will assess blood and expired gas concentrations using sequential blood samples from radial catheters and waveform capnography, respectively. We hypothesize that fatigue will be greater and O2 offloading at the muscle will be less in people with high Hb-O2 affinity compared to controls. Specific Aim 2 will test whether high Hb-O2 affinity will exacerbate exercise-induced metabolic accumulation and increase in perfusion to skeletal muscle. We will assess skeletal muscle bioenergetics via the accumulation of metabolic by-products produced from anaerobic metabolism (H+, Pi and H2PO4-) and (simultaneously) perfusion of blood to the exercising knee extensor muscles using interleaved phosphorous magnetic resonance spectroscopy (31P-MRS) and arterial spin labeling (ASL). We hypothesize that there will be a greater accumulation of exercise-related metabolites and hyperemic response in patients with high Hb-O2 affinity compared to controls. Specific Aim 3 will test whether physiological adaptations of skeletal muscle fiber type composition and mitochondrial oxidative capacity occur in people with high Hb-O2 affinity. We will assess skeletal muscle fiber myosin heavy chain expression and mitochondrial oxidative capacity using histochemical staining techniques (SDS-PAGE and silver staining) and high-resolution respirometry (Oxygraph-2k and Datlab software), respectively. We hypothesize that skeletal muscle fiber myosin heavy chain expression will be shifted toward higher proportions of glycolytic fibers and mitochondrial oxidative respiratory capacity will be reduced in people with high Hb-O2 affinity compared to controls. This proposal will test fundamental concepts related to the O2 transport cascade and exercising skeletal muscle in humans. The applicant and mentorship team, combined with the extensive resources at the Mayo Clinic, provide the optimal training environment to complete the proposed aims.

项目概要/摘要拟议工作的总体目标是研究有关骨骼肌的新颖转化想法该提案是在人体运动过程中氧气（O2）运输级联的表现。由优秀的导师团队提供支持，将为极具潜力的申请人提供重要的帮助支持他成为转化整合生理学独立研究者的目标。目标利用申请人在骨骼肌生理学方面的专业知识和独特的专业知识人类血流调节方面的功勋导师团队（赞助商，Joyner 博士）、骨骼肌和线粒体生物学（共同发起人，Lanza 博士）、骨骼肌成像技术（合作者，Port 博士）和血红蛋白 (Hb) 变体（合作者 Hoyer 博士和 Oliveira 博士）将测试是否高 Hb-。 O2 亲和力会加剧骨骼肌疲劳并减少骨骼肌在运动过程中的 O2 提取我们将评估持续最大 60 秒的膝伸肌疲劳程度。自愿等长收缩，我们将使用顺序评估血液和呼出气体浓度我们分别从桡动脉导管和波形二氧化碳图中获取血液样本，以消除疲劳。与对照组相比，Hb-O2 亲和力高的人的肌肉 O2 卸载量会更少。具体目标 2 将测试高 Hb-O2 亲和力是否会恶化运动引起的代谢骨骼肌灌注的积累和增加我们将评估骨骼肌生物能学。通过无氧代谢产生的代谢副产物（H+、Pi 和 H2PO4-）的积累，（同时）使用交错磷将血液灌注到锻炼膝关节伸肌我们发现，磁共振波谱 (31P-MRS) 和动脉自旋标记 (ASL) 将会存在。高 Hb-O2 患者运动相关代谢物和充血反应的积累更多与对照相比的亲和力。具体目标 3 将测试骨骼的生理适应。高 Hb-O2 人群的肌纤维类型组成和线粒体氧化能力我们将评估骨骼肌纤维肌球蛋白重链表达和线粒体氧化。使用组织化学染色技术（SDS-PAGE 和银染色）和高分辨率我们分别捕获了骨骼肌纤维。肌球蛋白重链表达将转向更高比例的糖酵解纤维和线粒体与对照组相比，Hb-O2 亲和力高的人的氧化呼吸能力会降低。该提案将测试与 O2 运输级联和锻炼骨骼肌相关的基本概念申请人和指导团队结合梅奥诊所的广泛资源，提供最佳的培训环境以完成拟议的目标。