AGING-ASSOCIATED ALTERATIONS IN CARDIAC MIF-AMPK SIGNALING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 心脏在衰老过程中发生的变化会导致心肌功能下降，使其更容易受到损害。心肌损伤的一个常见原因是缺血性损伤。到目前为止，缺乏将缺血应激耐受性下降与特定应激信号通路改变联系起来的实验证据。最近，我们发现巨噬细胞移动抑制因子(MIF)-AMP激活的蛋白激酶(AMPK)信号通路在限制缺血/再灌注引起的心脏损伤和功能障碍以及增龄性AMPK活性降低方面发挥着重要作用，这可能是导致骨骼肌线粒体功能降低和细胞内脂质代谢异常的一个重要因素。我们假设，衰老与心肌细胞激活宿主对急性缺血损伤的反应(MIF-AMPK级联反应)的能力下降有关，这导致对缺血损伤的耐受性降低。这些实验将检验MIF对老年心脏AMPK活性的正常化是否能减轻缺血/再灌流期间的损伤。我们概述了未来的实验，以检验调节行为，即热量摄入和运动，对老年心脏MIF-AMPK信号通路的影响，以阐明可能导致AMPK刺激的干预在老年人心血管疾病管理中的潜在作用。更好地了解随着年龄增长导致心脏AMPK活性变化的机制，对于充分了解老年人对缺血性损伤易感性增加的基础是重要的，并可能导致旨在限制心脏损伤的治疗策略。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alterations in the heart that occur during the aging process result in decreased myocardial function and render it more susceptible to damage. A common cause of damage to the myocardium is ischemic injury. Until now, experimental evidence linking a decline in ischemic stress tolerance to alterations in specific stress signaling pathways has been lacking. Recently, we have found that the macrophage migration inhibitory factor (MIF)-AMP-activated protein kinase (AMPK) signaling pathway plays an important role in limiting cardiac damage and dysfunction induced by ischemia/reperfusion, and aging-associated reduction in AMPK activity that may be an important contributing factor in the reduced mitochondrial function and dysregulated intracellular lipid metabolism associated with aging in skeletal muscles. We hypothesize that aging is associated with a decline in the ability of cardiac cells to activate this host response (MIF-AMPK cascades) to acute ischemic injury, which contributes to a reduced tolerance to ischemic insults. These experiments will examine whether normalization of AMPK activation by MIF in the aged heart mitigates injury during ischemia/reperfusion. We outline future experiments to examine the effect of modulating behaviors, namely caloric intake and exercise, on the MIF-AMPK signaling pathway in the aged heart, to elucidate the potential role of interventions that might lead to AMPK stimulation in managing cardiovascular disease in the elderly. Better understanding of the mechanisms leading to altered cardiac AMPK activation in response to ischemic stress with aging is important to fully understand the basis for increased susceptibility of the elderly to ischemic injury and could lead to therapeutic strategies aimed at limiting cardiac damage.