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.

围手术期的发病率和由于心脏病引起的死亡率是非心脏病的重要并发症 外科手术。在美国，每年约有2700万患者接受非心脏手术，有50例 成千上万的术后或术中心肌梗死（MI）。这个问题也很普遍 在我们国家的退伍军人中。具体而言，退伍军人卫生管理局进行了约40万手术 每年的程序以及从退伍军人事务外科质量改进计划中得出的数据 （VASQIP）表示在非心脏手术后发生的主要不良心血管事件（MACE） 大约5％ 手术肌钙蛋白海拔高度是术后死亡率的主要危险因素，发生在13.9％的退伍军人中 接受非心脏手术。 另一方面，体育锻炼是心血管风险最强大的修饰符之一， 对于那些有健康心脏的人和那些有厌恶心脏的人来说，这是可证明的受益。骨骼肌是 对于流动性至关重要，但也有一个新兴的理解，即它们产生和秘密细胞因子， 被称为“肌动物”，介导地方和系统性变化，以促进运动宽容和 整体健康。我们最近证明了肌动物肌蛋白会响应物理 活动和增强身体耐力。我们的初步数据还表明肌肉素的生产驱动 心肌能量适应以增加心脏应激抗性。基于这些发现 我们建议肌肉蛋白上调对于运动引起的心脏调节至关重要，并且这种效果 利用一旦定义的分子途径可能会用于治疗益处。 肌蛋白，也称为骨分泌蛋白，与心脂肪胡椒（NP）具有很高的同源性 对清除接收器NPRC的相当亲和力，但对Guanylyl环耦合的亲和力较低 受体NPRA和NPRB。通过对NPRC进化的竞争性干扰，肌肉素增加了 NP的局部浓度并增强其对环鸟嘌呤一磷酸（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鼠标模型并专门开发 生物测定确定肌肉整合骨骼肌和的分子机制 心肌自适应运动反应，以促进增强心脏所需的能量重塑 性能和压力抵抗。此外，该提案将评估合成肌肉输注的能力 模仿运动引起的一些好处，从而减少心脏遭受伤害的脆弱性。 这项研究的结果有望为发展新的心脏保护的发展提供基础 高风险患者的策略，例如由于无法进行运动或耐受性良好的患者的策略 疾病或受伤，需要压力大的手术或干预措施。