Introduction

Meteorin-like hormone (Metrnl) is ubiquitously expressed in skeletal muscle, heart, and adipose with beneficial roles in obesity, insulin resistance, and inflammation. Metrnl is found to protect against cardiac hypertrophy and doxorubicin-induced cardiotoxicity. However, its role in diabetic cardiomyopathy (DCM) is undefined.

Objectives

We aimed to elucidate the potential roles of Metrnl in DCM.

Methods

Gain- and loss-of-function experiments were utilized to determine the roles of Metrnl in the pathological processes of DCM.

Results

We found that plasma Metrnl levels, myocardial Metrnl protein and mRNA expressions were significantly downregulated in both streptozotocin (STZ)-induced (T1D) mice and leptin receptor deficiency (db/db) (T2D) mice. Cardiac-specific overexpression (OE) of Metrnl markedly ameliorated cardiac injury and dysfunction in both T1D and T2D mice. In sharp contrast, specific deletion of Metrnl in the heart had the opposite phenotypes. In parallel, Metrnl OE ameliorated, whereas Metrnl downregulation exacerbated high glucose (HG)-elicited hypertrophy, apoptosis and oxidative damage in primary neonatal rat cardiomyocytes. Antibody-induced blockade of Metrnl eliminated the effects of benefits of Metrnl in vitro and in vivo. Mechanistically, Metrnl activated the autophagy pathway and inhibited the cGAS/STING signaling in a LKB1/AMPK/ULK1-dependent mechanism in cardiomyocytes. Besides, Metrnl-induced ULK1 phosphorylation facilitated the dephosphorylation and mitochondrial translocation of STING where it interacted with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase that was responsible for ubiquitination and degradation of STING, rendering cardiomyocytes sensitive to autophagy activation.

Conclusion

Thus, Metrnl may be an attractive therapeutic target or regimen for treating DCM.

中文翻译：

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Metrnl 通过失活依赖于 LKB1/AMPK/ULK1 介导的自噬的 cGAS/STING 信号来改善糖尿病心肌病

介绍

镍纹蛋白样激素 (Metrnl) 广泛表达于骨骼肌、心脏和脂肪中，在肥胖、胰岛素抵抗和炎症中发挥有益作用。Metrnl 被发现可以防止心脏肥大和阿霉素诱导的心脏毒性。然而，其在糖尿病心肌病（DCM）中的作用尚不清楚。

目标

我们的目的是阐明 Metrnl 在 DCM 中的潜在作用。

方法

利用功能获得和 丧失实验 来确定 Metrnl 在 DCM 病理过程中的作用。

结果

我们发现链脲佐菌素 (STZ) 诱导的 (T1D) 小鼠和瘦素受体缺陷 (db/db) (T2D) 小鼠的血浆 Metrnl 水平、心肌 Metrnl 蛋白和 mRNA 表达显着下调。Metrnl 的心脏特异性过表达 (OE) 显着改善了 T1D 和 T2D 小鼠的心脏损伤和功能障碍。与此形成鲜明对比的是，心脏中Metrnl的特异性缺失具有相反的表型。与此同时，Metrnl OE 得到改善，而 Metrnl 下调则加剧了高糖 (HG) 引起的原代新生大鼠心肌细胞肥大、细胞凋亡和氧化损伤。抗体诱导的 Metrnl 阻断消除了 Metrnl在体外和体内的益处的影响。从机制上讲，Metrnl 激活自噬途径并抑制心肌细胞中 LKB1/AMPK/ULK1 依赖性机制中的 cGAS/STING 信号传导。此外，Metrnl诱导的ULK1磷酸化促进了STING的去磷酸化和线粒体易位，其中它与肿瘤坏死因子受体相关因子2（TRAF2）相互作用，TRAF2是一种支架蛋白和E3泛素连接酶，负责STING的泛素化和降解，使心肌细胞对自噬激活敏感。

结论

因此，Metrn1可能是治疗DCM的有吸引力的治疗靶点或方案。