From the Cardiovascular Research Center (M.S., J.C.P., C.K., L.K., J.J., A.P., T.W., E.M., J.Y.P., F.A.R.) and the Center for Translational Medicine (S.R.), Lewis Katz School of Medicine at Temple University, Philadelphia, PA; Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (S.M., M.A.Z., C.-L.W., K.W.); Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy (F.A.R.); and Fondazione Toscana Gabriele Monasterio, Pisa, Italy (F.A.R.).
Circ Heart Fail. 2018 Jan;11(1):e004486. doi: 10.1161/CIRCHEARTFAILURE.117.004486.
FSTL1 (follistatin-like protein 1) is an emerging cardiokine/myokine that is upregulated in heart failure (HF) and is found to be cardioprotective in animal models of cardiac injury. We tested the hypothesis that circulating FSTL1 can affect cardiac function and metabolism under baseline physiological conditions and in HF.
FSTL1 was acutely (10 minutes) or chronically (2 weeks) infused to attain clinically relevant blood levels in conscious dogs with cardiac tachypacing-induced HF. Dogs with no cardiac pacing and FSTL1 infusion served as control. H-oleate and C-glucose were infused to track the metabolic fate of free fatty acids and glucose. Cardiac uptake of lactate and ketone bodies and systemic respiratory quotient were also measured. HF caused a shift from prevalent cardiac and systemic fat to carbohydrate oxidation. Although acute FSTL1 administration caused minimal hemodynamic changes at baseline, in HF dogs it enhanced cardiac oxygen consumption and transiently reversed the changes in free fatty acid and glucose oxidation and systemic respiratory quotient. In HF, chronic FSTL1 infusion stably normalized cardiac free fatty acid, glucose, ketone body consumption, and systemic respiratory quotient, while moderately improving diastolic and contractile function. Consistently, FSTL1 prevented the downregulation of medium-chain acyl-CoA dehydrogenase-a representative enzyme of the free fatty acid oxidation pathway. Complementary in vitro experiments in primary cardiac and skeletal muscle myocytes showed that FSTL1 stimulated oxygen consumption through AMPK (AMP-activated kinase) activation.
These findings support a novel function for FSTL1 and provide the first direct evidence that a circulating cardiokine/myokine can alter myocardial and systemic energy substrate metabolism, in vivo.
FSTL1（卵泡抑素样蛋白 1）是一种新兴的心脏激素/肌肉激素，在心力衰竭（HF）中上调，并在心脏损伤的动物模型中被发现具有心脏保护作用。我们检验了这样一个假设，即在基础生理条件下和心力衰竭时，循环 FSTL1 可以影响心脏功能和代谢。
在伴有心脏起搏诱导心力衰竭的清醒犬中，急性（10 分钟）或慢性（2 周）输注 FSTL1，以达到临床相关的血液水平。没有心脏起搏和 FSTL1 输注的犬作为对照。输注 H-油酸盐和 C-葡萄糖来追踪游离脂肪酸和葡萄糖的代谢命运。还测量了心脏对乳酸和酮体的摄取以及全身呼吸商。HF 导致从主要的心脏和全身脂肪向碳水化合物氧化转变。尽管急性 FSTL1 给药在基础状态下引起最小的血液动力学变化，但在 HF 犬中，它增强了心脏耗氧量，并短暂逆转了游离脂肪酸和葡萄糖氧化以及全身呼吸商的变化。在 HF 中，慢性 FSTL1 输注稳定地使心脏游离脂肪酸、葡萄糖、酮体消耗和全身呼吸商正常化，同时适度改善舒张和收缩功能。一致地，FSTL1 防止了中链酰基辅酶 A 脱氢酶的下调 - 游离脂肪酸氧化途径的代表性酶。在原代心脏和骨骼肌肌细胞中的补充体外实验表明，FSTL1 通过 AMPK（AMP 激活的蛋白激酶）激活刺激耗氧量。
这些发现支持 FSTL1 的新功能，并提供了第一个直接证据，表明一种循环心脏激素/肌肉激素可以改变心肌和全身能量底物代谢，在体内。
