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源性心脏病的重要并发症， 手术在美国，每年约有2700万患者接受非心脏手术，其中50 1000名患者患有术后或术中心肌梗死（MI）。这个问题也非常普遍 在我们国家的退伍军人中。具体来说，退伍军人健康管理局进行了大约40万例手术， 每年的手术，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，非心脏手术后发生的主要心血管不良事件（MACE） 约5%，而另一项研究表明，心肌损伤表明，无症状后， 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， 这两个人，都是心有灵犀，心有灵犀的人。骨骼肌是 对于移动性至关重要，但也有一种新兴的理解，即它们产生和分泌细胞因子， 称为“肌因子”，其介导局部和全身变化以促进运动耐受性， 整体健康。我们最近证明，肌因子musclin是上调，以响应物理 活动和增强身体耐力。我们的初步数据还表明，肌肉蛋白的产生驱动着 增加心脏抗应激能力所必需的心肌能量适应。基于这些发现 我们认为，肌肉蛋白的上调对于运动诱导的心脏调节是至关重要的， 利用分子途径，一旦确定，可以利用治疗效益。 肌蛋白，也称为骨蛋白，与心脏利钠肽（NP）具有高度同源性， 对清除受体NPRC的亲和力相当，但对鸟苷酸环化酶偶联的NPRC的亲和力低。 受体，NPRA和NPRB。通过竞争性干扰消除在NPRC，肌肉增加 NPs的局部浓度，并增强其对环磷酸鸟苷（cGMP）合成的影响 - 一个重要的细胞内信使该项目将使用独特的遗传小鼠模型和专门开发的 通过生物测定来确定肌肉蛋白整合骨骼肌的分子机制， 心肌适应性运动反应，以促进增强心脏所需的能量重塑 性能和抗应力。此外，该提案将评估合成肌肉注射的能力， 模仿运动带来的一些好处，从而减少心脏对损伤的脆弱性。 本研究的结果有望为开发新的心脏保护剂提供基础。 高风险患者的策略，例如那些由于以下原因而无法锻炼或耐受良好的患者 疾病或受伤，以及需要压力手术或干预的人。