Walk this way: leveraging of a unique skeletal muscle that is resistant to ischemic injury

沿着这条路走：利用独特的抗缺血性损伤的骨骼肌

• 批准号: 10242213
• 负责人: ESPEN E SPANGENBURG
• 金额: $ 35.63万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-19 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242213
• 关键词: ATP Hydrolysis; Acute; Address; Adenosine Triphosphate; Affect; Age; Annexins; Binding Proteins; Biochemical; Bioenergetics; Biological; Blood flow; Cells; Charge; Clinical; Compartment syndromes; Coronary Occlusions; Data; Development; Distal; Drops; Dyes; Ensure; Evans blue stain; Exhibits; Experimental Designs; Exposure to; Flexor; Free Energy; Generations; Genes; Genetic; Glycogen; Goals; Grant; Hemorrhage; Hindlimb; Hour; Human; Hypoxia; Ischemia; Limb structure; Longevity; Maintenance; Membrane; Metabolic; Modeling; Molecular; Muscle; Muscle function; Myoblasts; Myocardium; Myopathy; Necrosis; Oxygen; Pathology; Patients; Peripheral; Peripheral arterial disease; Phenotype; Physiological; Play; Pre-Clinical Model; Predisposition; Production; Proteins; Proteomics; Reaction; Regulation; Resistance; Role; SLC2A1 gene; Sarcolemma; Site; Skeletal Muscle; Soleus Muscle; System; Therapeutic; Tissue Survival; Tissues; Walking; artery occlusion; base; design; excitotoxicity; experience; experimental study; extensor digitorum; femoral artery; functional independence; gain of function; improved; in vivo; ischemic injury; limb injury; limb ischemia; loss of function; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; preservation; prevent; skeletal muscle wasting; therapeutic target

Abstract/Project Summary Dogma tells us that oxygen (O2) is an absolute requirement for cell/tissue survival. We have recently discovered a unique skeletal muscle that is remarkably and uniquely resistant to negative effects of ischemia. The implication is that unlike other peripheral skeletal muscles, this muscle has a distinct mechanism that allows it to tolerate ischemic conditions. Identifying the underlying mechanism(s) that explain the ischemia resistance could hold the key to unlocking therapeutic targets and/or approaches for improving tissue survival under conditions where O2 exposure is limiting. Ischemia affects skeletal muscle in numerous clinical conditions, including various myopathies, peripheral artery disease (PAD), compartment syndrome, severe limb injury, etc., not to mention coronary occlusion in cardiac muscle. Thus, the identification of a mechanism that provides ischemia resistance would overcome one of the longest standing challenges faced by clinicians. Using an integrative experimental design, the scientific goal of this project is to elucidate the unique functional, metabolic, and/or bioenergetic systems that account for the ability of this muscle to survive ischemic insults. The long-term goal of the project is to leverage the identified mechanism(s) to therapeutically treat and/or prevent myopathies induced or exacerbated by ischemia. The proposal will use molecular, biochemical, and physiological approaches designed to address hypotheses grounded in the idea that this unique muscle must be able to meet energetic demands and ensure sarcolemmal stability during ischemia. Thus, the experimental approach seeks to leverage already identified genes that are critical to the generation of adenosine triphosphate and manipulate genes that are able to stabilize the sarcolemma during ischemic conditions to prevent excitotoxicity. Using gain-of or loss-of function approaches the experiments designed in the proposal will determine if the mechanism is necessary for ischemia survival and also assess if the mechanism is sufficient to survive ischemia. Completion of this proposal will challenge dogma concerning our understanding of how tissue can resist ischemic insults and advance the field forward in a significant fashion due to the identification of an ischemia-resistant muscle.

摘要/项目摘要 教条告诉我们，氧气（O2）是细胞/组织生存的绝对必需品。我们最近 发现了一种独特的骨骼肌，它对局部缺血的负面影响有着显著而独特的抵抗力。 这意味着，与其他外周骨骼肌不同，这种肌肉有一种独特的机制， 使其能够耐受缺血性条件。确定解释缺血的潜在机制 耐药性可能是打开治疗靶点和/或改善组织存活的方法的关键 在氧气暴露受到限制的条件下。缺血影响骨骼肌在许多临床 疾病，包括各种肌病、外周动脉疾病（PAD）、筋膜室综合征、严重 肢体损伤等，更不用说心肌中的冠状动脉阻塞了。因此，确定一种机制 提供抗局部缺血性将克服临床医生面临的最长期的挑战之一。 使用综合实验设计，该项目的科学目标是阐明独特的 功能、代谢和/或生物能量系统，这些系统解释了这种肌肉在缺血性损伤中存活的能力。 侮辱。该项目的长期目标是利用已确定的机制来治疗 和/或预防由局部缺血诱发或加重的肌病。该提案将使用分子，生物化学， 和生理学方法来解决基于这种独特的肌肉 必须能够满足能量需求并确保局部缺血期间肌膜的稳定性。因此 实验方法试图利用已经确定的基因，这些基因对产生 腺苷三磷酸和操纵基因，能够稳定肌膜在缺血 防止兴奋性毒性的条件。使用增益或损失的功能方法的实验设计， 该提案将确定该机制是否是缺血存活所必需的， 机制足以在缺血中存活。完成这项建议将挑战有关我们的教条， 了解组织如何能够抵抗缺血性损伤，并以一种重要的方式向前推进该领域 这是由于抗缺血肌肉的鉴定。

项目成果

Hypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle.

• DOI: 10.1093/function/zqad012
• 发表时间: 2023
• 期刊: Function (Oxford, England)

Skeletal muscle undergoes fiber type metabolic switch without myosin heavy chain switch in response to defective fatty acid oxidation.

• DOI: 10.1016/j.molmet.2022.101456
• 发表时间: 2022-05
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Pereyra AS;Lin CT;Sanchez DM;Laskin J;Spangenburg EE;Neufer PD;Fisher-Wellman K;Ellis JM
• 通讯作者: Ellis JM