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

• 批准号: 10062667
• 负责人: Jonathon Senefeld
• 金额: $ 6.49万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-26 至 2022-05-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062667
• 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

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.

项目摘要/摘要 拟议工作的总体目标是调查有关骨骼肌肉的新型翻译思想 在人类运动过程中氧气（O2）的背景下的性能。该提议是 得到一支杰出的训练团队的支持，将为备受希望的申请人提供重要的重要 支持他成为翻译综合生理学的独立研究者的目标。具体 目的利用申请人在骨骼肌生理方面的专业知识以及独特的专业知识 人类血液流量调节（赞助商，乔伊纳博士），骨骼肌和 线粒体生物学（Lanza博士共同发起人），骨骼肌肉成像技术（合作者，博士）和 血红蛋白（HB）变体（合作者，Hoyer博士和Oliveira）。特定目标1将测试高HB-是否是否 O2亲和力会加剧骨骼肌疲劳，并减少骨骼肌肉O2提取。 疲劳运动。我们将评估持续的60 s最大膝关节肌肉的疲劳 自愿等距收缩，我们将使用顺序评估血液和过期的气体浓度 分别来自径向导管和波形胶囊的血液样本。我们假设疲劳会 与对照组相比，HB-O2亲和力较高的人的肌肉中的O2卸载量更少。 特定目标2将测试高HB-O2亲和力是否会加剧运动诱导的代谢 积累并增加骨骼肌的灌注。我们将评估骨骼肌肉生物能力 通过厌氧代谢（H+，PI和H2PO4-）产生的代谢副产品的积累和 （同时）使用交织的磷灌注血液至运动膝关节肌肉 磁共振光谱（31p-MR）和动脉自旋标记（ASL）。我们假设会有 在高HB-O2患者中，与运动相关的代谢产物的积累更大 与对照组相比，亲和力。特定目标3将测试骨骼的身体适应 肌肉纤维类型组成和线粒体氧化能力在HB-O2高的人中发生 亲和力。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和银色染色）和高分辨率的容量 呼吸测定法（OxyGraph-2K和Datlab软件）。我们假设骨骼肌纤维 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亲和力高的人将降低氧化呼吸能力。这 提案将测试与O2运输级联和运动骨骼肌有关的基本概念 人类。申请人和心态团队，加上梅奥诊所的广泛资源， 提供最佳的培训环境来完成拟议的目标。