Aims Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A. Methods and results Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure. Conclusion Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.

中文翻译：

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GDF15 拮抗作用可限制严重心力衰竭并预防心脏恶病质


目的 心力衰竭和相关的恶病质是一个尚未解决的重要问题。本研究旨在确定在缺乏综合应激反应 (ISR) 诱导的 eIF2α 磷酸酶 PPP1R15A 的小鼠新心力衰竭模型中导致心脏恶病质的因素。方法和结果对小鼠进行辐射并用骨髓细胞进行重建。缺乏功能性 PPP1R15A 的小鼠在辐射后表现出扩张型心肌病和严重的体重减轻，而野生型小鼠则不受影响。这与心脏中 GDF15 表达的增加以及循环中 GDF15 水平的增加有关。我们提供的证据表明，阻断 GDF15 活性可以预防恶病质并减缓心力衰竭的进展。我们还展示了 GDF15 与心力衰竭患者去脂体重和蛋白质摄入量的相关性。结论 我们的数据表明，心脏应激介导 GDF15 依赖性途径，导致体重减轻并恶化心脏功能。阻断 GDF15 可能构成一种新的治疗选择，以限制心脏恶病质并改善严重收缩性心力衰竭患者的临床结果。