Does Exercise Induce Cardiomyogenesis?

描述（由申请人提供）：成人心脏没有再生或心肌形成能力的传统观点受到质疑，现在有多种证据支持心脏再生的一些潜力，尽管有限。然而，我们对调节这种再生能力的生理过程和途径的理解存在根本性的差距。这个差距代表了一个重要的问题，因为它限制了我们利用心脏的再生能力来恢复疾病中的心脏功能的能力。长期目标是了解调节心脏再生的机制，并学习如何控制它。当前应用的目的是了解运动诱导心肌形成的机制和贡献。申请人实验室的初步数据表明，运动可以诱导心脏产生潜在的再生反应。这些研究还发现了一种新的转录途径，包括共激活因子CITED4，它是心脏运动反应的关键介质。这一建议基于三个核心假设：1)运动增强了心脏的内源性再生能力；2) CITED4对于运动诱导的心肌生成是必需的；3) cited4依赖性心肌生成有助于基线和疾病时运动的益处。该建议的基本原理是，了解调节心脏内源性再生能力的生理机制，将推动利用这种能力治疗与心肌细胞丧失相关的临床重要疾病的努力。中心假设将在三个综合的具体目标中进行测试。在Aim 1中，一项最近开发的技术将遗传命运定位与基于质谱的成像（多同位素成像质谱或MIMS）相结合，用于明确识别两种运动模式中形成的新心肌细胞的数量、来源和命运。在Aim 2中，将在基线和运动中确定心肌细胞和表达c-kit的心脏祖细胞中谱系特异性CITED4失活的后果。在Aim 3中，将研究运动诱导的心肌生成减轻心肌梗死后重构的能力，以及是否需要使用CITED4。体内研究将通过体外分离细胞群的研究来支持，包括成人心肌细胞和表达c-kit的心脏祖细胞，以阐明潜在的机制。该方法结合了创新的假设、技术和独特的动物模型，以及一个杰出的合作研究团队的互补专业知识。这项提议的研究意义重大，因为它有望推进我们对心脏再生、运动的好处以及它们减轻疾病的潜力的理解。这些研究将提供新的

DESCRIPTION (provided by applicant): The traditional view that the adult heart has no capacity for regeneration or cardiomyogenesis has been called into question, and multiple lines of evidence now support some albeit limited potential for cardiac regeneration. However, there is a fundamental gap in our understanding of the physiological processes and pathways that regulate this regenerative capacity. This gap represents an important problem because it limits our ability to exploit the heart's regenerative capacity to restore cardiac function in disease. Th long-term goal is to understand the mechanisms regulating cardiac regeneration and to learn how to control it. The objective of the current application is to understand the mechanisms and contribution of exercise-induced cardiomyogenesis. Preliminary data produced in the applicants' laboratories suggest that exercise induces a potentially regenerative response in the heart. These studies also identify a new transcriptional pathway, including the co-activator, CITED4, as a key mediator of the cardiac exercise response. This proposal is based on three central hypotheses: 1) that exercise enhances the endogenous regenerative capacity of the heart; 2) that CITED4 is necessary for exercise-induced cardiomyogenesis; and 3) that CITED4-dependent cardiomyogenesis contributes to the benefits of exercise at baseline and in disease. The rationale for the proposal is that understanding the physiological mechanisms regulating the heart's endogenous regenerative capacity will advance efforts to therapeutically harness this capacity for clinically important conditions associated with loss of cardiomyocytes. The central hypotheses will be tested in three integrated Specific Aims. In Aim 1, a recently developed technology that combines genetic fate mapping with mass spectrometry-based imaging (Multi-isotope Imaging Mass Spectrometry or MIMS) will be used to unambiguously identify the number, source, and fate of new cardiomyocytes formed in two models of exercise. In Aim 2, the consequences of lineage-specific CITED4 inactivation in cardiomyocytes and c-kit-expressing cardiac progenitor cells will be determined at baseline and in exercise. In Aim 3, the ability of exercise-induced cardiomyogenesis to mitigate remodeling after myocardial infarction and whether CITED4 is required will be examined. In vivo studies will be supported by in vitro investigation of isolated cell populations including adult cardiomyocytes and c-kit-expressing cardiac progenitor cells to elucidate the underlying mechanisms. The approach combines innovative hypotheses, technologies, and unique animal models with the complementary expertise of an outstanding team of collaborating investigators. The proposed research is significant, because it is expected to advance our understanding of cardiac regeneration and the benefits of exercise as well as their potential to mitigate disease. These studies will provide new insights into the physiological mechanisms controlling cardiac growth and regeneration as well as informing therapeutic approaches to diseases associated with cardiomyocyte loss such as heart failure and ischemic heart disease.