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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.

项目总结/文摘