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: 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
• 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

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 这项拟议工作的总体目标是研究有关骨骼肌的新的翻译思想 在人类运动过程中，氧(O2)运输级联的表现。该提案是 由杰出的指导团队提供支持，并将为非常有前途的申请者提供重要的 支持他成为翻译综合生理学的独立研究员的目标。具体的 旨在利用申请者在骨骼肌生理学方面的专业知识和 关于人类血液流动调节的功勋导师团队(赞助商，乔伊纳博士)，骨骼肌和 线粒体生物学(共同发起人，兰扎博士)、骨骼肌成像技术(合作者，波特博士)和 血红蛋白(Hb)变体(合作者，Hoyer和Oliveira博士)。特定目标1将测试高Hb- 氧亲和力会加剧骨骼肌疲劳，减少骨骼肌氧摄取 疲惫的运动。我们将评估持续的膝关节伸肌疲劳，60-S最大 自愿等长收缩，我们将评估血液和呼出气体的浓度 分别从放射状导管和波形二氧化碳描记术中采集血样。我们假设疲劳会 与对照组相比，Hb-O2亲和力高的人肌肉中的O2卸载会更少。 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 骨骼肌的蓄积和灌流增加。我们将评估骨骼肌生物能量学 通过积累厌氧代谢产生的代谢副产物(H+、PI和H2PO4-)和 (同时)使用交错磷对锻炼的膝关节伸肌进行血液灌流 磁共振波谱(31P-MRS)和动脉自旋标记(ASL)。我们假设会有 高Hb-O2患者运动相关代谢物积聚和充血反应增加 与对照相比的亲和力。特定目标3将测试骨骼的生理适应 高Hb-O2人群的肌肉纤维类型组成和线粒体氧化能力 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 利用组织化学染色技术(SDS-PAGE和银染)和高分辨率 呼吸测量(Oxygraph-2k和DatLab软件)。我们假设骨骼肌纤维 肌球蛋白重链的表达将向更高比例的糖酵解纤维和线粒体转移 与对照组相比，Hb-O2亲和力高的人的氧化呼吸能力会降低。这 该提案将测试与氧气转运级联和锻炼骨骼肌相关的基本概念 人类。申请者和指导团队，加上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。