Follistatin-like protein 1 in cardiac and systemic metabolism

 描述(申请人提供)：来自我们实验室和其他实验室的最新研究表明，心脏和外周之间存在复杂的能量底物代谢的交叉调节，这种调节是由添加到胰岛素、胰高血糖素或其他经典调节因子的多肽/蛋白质介导的。在潜在的候选介质中，特别值得关注的是肌肉释放的荷尔蒙样因子，统称为“肌肉激动素”。其中一个新出现的成员是卵泡抑素样蛋白1(FSTL1)，它也是由心脏产生的，正如第一次显示的那样 由沃尔什实验室发现，因此可归因于名为“心脏因子”的肌细胞因子亚群。高循环FSTL1是心力衰竭(HF)的可靠标志，而如果急性 FSTL1过表达可保护心脏免受缺血再灌注损伤。然而，尽管FSTL1的分子生物学甚至治疗潜力正在被逐步阐明和定义，但关于这种激素的综合生理学和病理生理学几乎还不清楚。特别是，还没有研究探索FSTL1作为代谢调节剂的潜在作用。雷奇亚和沃尔什实验室的初步研究表明，FSTL1的过度表达或输注改变了小鼠和狗的心脏和系统代谢。因此，本项目将检验这一假说，即心脏和骨骼肌产生的FSTL1的相对部分因生理和病理条件的不同而不同，并按比例参与心脏和全身能量代谢的自分泌和相互内分泌调节。结合对狗和老鼠模型的研究，将追求三个具体目标。具体目标1将确定心肌和骨骼肌在基线和对运动或中、重度心衰的反应时的总周转率和FSTL1的相对生成率。这些研究将在长期使用仪器的狗身上进行，在休息条件下和在运动期间或在快速跳动引起的心衰的发展过程中进行。具体目标2将测试FSTL1是否在生理条件下和在HF中调节心脏和全身的氧和能量底物消耗。这些研究将在心肌或骨骼肌选择性FSTL1功能丧失的小鼠模型和慢性仪器化的狗身上进行。潜在的分子变化和机制将在体外组织样本以及暴露于FSTL1的培养心肌细胞和骨骼肌纤维中确定。具体目标3将测试持续、选择性地增强心脏FSTL1合成是否可以减轻心肌和/或全身代谢变化，并在心力衰竭中发挥治疗作用。这些研究将在心脏特异的FSTL1基因敲除小鼠中进行，这些小鼠受到主动脉收缩的影响，以及患有心动过速诱发的心力衰竭的狗，并接受由腺相关病毒载体携带的FSTL1心脏基因转移。在小鼠和狗身上进行的联合研究可能会导致将新的发现转化为治疗心力衰竭的新生物疗法。

 DESCRIPTION (provided by applicant): Recent studies from our laboratory and others suggest the existence of a complex cross- regulation of energy substrate metabolism between heart and periphery, mediated by peptides/proteins that add to insulin, glucagon or other classical regulators. Among the potential candidate mediators, particular attention deserve muscle-released, hormone-like factors collectively named "myokines". One of the emerging members is follistatin-like protein 1 (Fstl1), which is produced also by the heart, as first showed by the Walsh laboratory, and can be therefore ascribed to the myokine subgroup named "cardiokines". High circulating Fstl1 is a reliable marker of heart failure (HF), while, if acutely overexpressed, Fstl1 can protect the heart against ischemia-reperfusion injury. However, while the molecular biology and even the therapeutic potential of Fstl1 are being progressively elucidated and defined, virtually nothing is known yet about the integrative physiology and pathophysiology of this hormone. In particular, no studies have explored the potential role of Fstl1 as a metabolic modulator. Preliminary studies from Recchia and Walsh labs indicate that Fstl1 overexpression or infusion alters cardiac and systemic metabolism in mice and dogs. Therefore the present project will test the hypothesis that the relative fractions of Fstl1 produce by heart and skeletal muscle vary in response to physiological and pathological conditions and contribute proportionally to the autocrine and the reciprocal endocrine regulation of cardiac and systemic energy metabolism. Three specific aims will be pursued combining studies in dog and mouse models. Specific aim 1 will determine overall turnover and relative rate of Fstl1 production by cardiac and skeletal muscle at baseline and in response to exercise or to moderate and severe HF. These studies will be performed in chronically instrumented dogs under resting conditions and during exercise or the development of tachypacing-induced HF. Specific aim 2 will test whether Fstl1 modulates cardiac and systemic oxygen and energy substrate consumption under physiological conditions and in HF. These studies will be performed in mouse models of cardiac or skeletal muscle- selective Fstl1 loss of function and in chronically instrumented dogs. The underlying molecular changes and mechanisms will be determined in tissue samples, ex vivo, as well as in cultured cardiomyocytes and skeletal myofibers exposed to Fstl1. Specific aim 3 will test whether sustained, selective enhancement of cardiac Fstl1 synthesis can attenuate myocardial and/or systemic metabolic alterations and exert therapeutic effects in HF. These studies will be performed in cardio-specific Fstl1 knockout mice subjected to aortic constriction and in dogs with tachypacing-induced HF and subjected to cardiac gene transfer of Fstl1 carried by adeno- associated viral vectors. Combined studies in mice and dogs may lead to the translation of novel findings into a new biological therapy for HF.