Myokine musclin and exercise induced cardiac conditioning

肌动蛋白和运动诱导的心脏调节

• 批准号: 10553168
• 负责人: Leonid Zingman
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553168
• 关键词: Accounting; Address; Affinity; Animals; Apoptosis; Binding Proteins; Biological Assay; Cardiac; Cardiovascular system; Cessation of life; Complement; Coupled; Cyclic GMP; Data; Development; Disease; Endocrine; Endocrine Glands; Event; Exercise; Exercise Physiology; Exercise Tolerance; Exhibits; Foundations; Future; Genes; Genetic; Guanylate Cyclase; Health; Heart; Heart Arrest; Heart Diseases; Hospitals; Infusion procedures; Injury; Intervention; Mediating; Mitochondria; Modeling; Molecular; Mus; Muscle; Myocardial; Myocardial Infarction; NPR2 gene; Natriuretic Peptides; OPA1 gene; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patients; Peptides; Performance; Persons; Physical Endurance; Physical activity; Physiological; Postoperative Period; Prevention strategy; Process; Production; Reporting; Resistance; Response Elements; Risk; Risk Factors; Role; Signal Transduction; Skeletal Muscle; Stress; Supplementation; Surgical complication; Therapeutic; Tissues; Training; Training Support; Troponin; United States; United States Department of Veterans Affairs; Up-Regulation; Veterans; Veterans Health Administration; cardioprotection; cardiovascular risk factor; comorbidity; conditioning; cytokine; disorder prevention; efficacy evaluation; energy efficiency; exercise capacity; exercise training; experimental study; high risk; improved; ischemic injury; mortality; mouse model; myocardial injury; novel; novel strategies; perioperative morbidity; perioperative mortality; programs; protective effect; receptor; response; surgical risk; treadmill; treatment strategy

Perioperative morbidity and mortality due to heart disease are important complications of non-cardiac surgery. In the United States approximately 27 million patients undergo non-cardiac surgery annually, with 50 thousand suffering a post- or intra-operative myocardial infarction (MI). The problem is also highly prevalent among our nation’s veterans. Specifically, the Veterans Health Administration performs about 400,000 surgical procedures per year, and data derived from the Veterans Affairs Surgical Quality Improvement Program (VASQIP) indicate that major adverse cardiovascular events (MACE) after non-cardiac surgeries occur in approximately 5%, while another study indicates that myocardial injury indicated by asymptomatic post- operative troponin elevation, a major risk factor for post-operative mortality, occurs in 13.9% of veterans undergoing non-cardiac surgery. On the other hand physical activity is one of the most powerful modifiers of cardiovascular risk, with proven benefits both for those with healthy hearts and for those with diseased hearts. Skeletal muscles are critical for mobility, but there is also an emerging understanding that they produce and secrete cytokines, termed “myokines”, which mediate local and systemic changes in order to promote exercise tolerance and overall health. We recently demonstrated that the myokine musclin is upregulated in response to physical activity and augments physical endurance. Our preliminary data also indicate that musclin production drives the myocardial energetic adaptation necessary to increase cardiac stress resistance. Based on these findings we propose that musclin upregulation is critical for exercise-induced cardiac conditioning and that this effect utilizes molecular pathways that, once defined, may be harnessed for therapeutic benefit. Musclin, also known as osteocrin, has high homology to the cardiac natriuretic peptides (NP) with comparable affinity for the clearance receptor, NPRC, but low affinity for the guanylyl cyclase-coupled receptors, NPRA and NPRB. Through competitive interference for elimination at NPRC, musclin increases the local concentration of NPs and augments their effect on synthesis of cyclic guanosine monophosphate (cGMP) - a critical intracellular messenger. This project will use unique genetic mouse models and specially developed bioassays to determine the molecular mechanisms by which musclin integrates skeletal muscle and myocardial adaptive exercise responses to promote the energetic remodeling necessary for enhanced cardiac performance and stress resistance. Further, the proposal will assess the ability of synthetic musclin infusion to mimic some of the benefits triggered by exercise and thereby reduce vulnerability of the heart to injury. Findings from this study are expected to provide a foundation for development of novel cardioprotective strategies for high-risk patients, such as those for whom exercise is not possible or well-tolerated due to illnesses or injuries, and who require stressful surgeries or interventions.

心脏病引起的围手术期发病率和死亡率是非心脏疾病的重要并发症 在美国，每年约有 2700 万名患者接受非心脏手术，其中 50 名患者接受非心脏手术。 数以千计的人在手术后或术中患有心肌梗塞（MI），这个问题也非常普遍。 具体来说，退伍军人健康管理局在我们国家的退伍军人中进行了约 400,000 例手术。 每年的程序以及来自退伍军人事务部手术质量改进计划的数据 （VASQIP）表明非心脏手术后主要不良心血管事件（MACE）发生在 大约 5%，而另一项研究表明，无症状的术后心肌损伤表明 手术肌钙蛋白升高是术后死亡的主要危险因素，发生在 13.9% 的退伍军人中 接受非心脏手术。 另一方面，体力活动是心血管风险最有力的调节因素之一， 已证实对心脏健康的人和骨骼肌患病的人都有好处。 对于流动性至关重要，但人们也逐渐认识到它们会产生和分泌细胞因子， 称为“肌因子”，它介导局部和全身变化，以促进运动耐量和 我们最近证明肌因子肌肉蛋白会因身体反应而上调。 我们的初步数据还表明，肌肉的产生会促进运动。 基于这些发现，心肌能量适应是增加心脏应激抵抗力所必需的。 我们认为肌肉蛋白上调对于运动诱发的心脏调节至关重要，并且这种作用 利用分子途径，一旦定义，就可用于治疗益处。 肌肉蛋白，也称为骨分泌蛋白，与心钠尿肽 (NP) 具有高度同源性， 对清除受体 NPRC 具有相当的亲和力，但对鸟苷酸环化酶偶联的亲和力较低 通过竞争性干扰消除 NPRC 受体，NPRA 和 NPRB，肌肉会增加 NP 的局部浓度并增强其对环磷酸鸟苷 (cGMP) 合成的影响 - 关键的细胞内信使该项目将使用独特的遗传小鼠模型并专门开发。 生物测定以确定肌肉蛋白整合骨骼肌和肌肉的分子机制 心肌适应性运动反应，以促进增强心脏功能所需的能量重塑 此外，该提案还将评估合成肌肉蛋白输注的能力。 模仿运动带来的一些好处，从而减少心脏受伤的可能性。 这项研究的结果有望为新型心脏保护剂的开发提供基础 针对高风险患者的策略，例如由于以下原因而无法或无法进行运动的患者 疾病或受伤，以及需要压力较大的手术或干预的人。