Background 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.

Methods and Results 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. ³H-oleate and ¹⁴C-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.

Conclusions 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.

背景技术FSTL1（类卵泡抑素蛋白1）是一种新兴的心因子/肌因子，在心力衰竭（HF）中被上调，并且在心脏损伤的动物模型中具有心脏保护作用。我们测试了在基线生理条件下和HF中循环FSTL1会影响心脏功能和代谢的假说。

方法和结果FSTL1急性输注（10分钟）或慢性输注（2周），以达到在心动过速引起的HF的清醒犬中达到临床相关的血药浓度。无心脏起搏和FSTL1输注的狗作为对照。³ H-油酸酯和¹⁴注入C-葡萄糖以追踪游离脂肪酸和葡萄糖的代谢命运。还测量了乳酸和酮体的心脏摄取和全身呼吸商。HF引起了心脏和全身脂肪向碳水化合物氧化的转变。尽管急性FSTL1给药在基线时引起的血液动力学变化最小，但在HF狗中，它增加了心脏耗氧量，并暂时逆转了游离脂肪酸，葡萄糖氧化和全身呼吸商的变化。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恢复正常，同时适度改善舒张和收缩功能。始终如一 FSTL1阻止了中链酰基辅酶A脱氢酶（一种游离脂肪酸氧化途径的代表酶）的下调。在原代心脏和骨骼肌心肌细胞中进行的补充体外实验表明，FSTL1通过AMPK（AMP激活的激酶）激活来刺激耗氧量。

结论这些发现支持FSTL1的新功能，并提供了直接的直接证据，表明循环中的心动因子/肌动蛋白可以在体内改变心肌和全身能量底物的代谢。