Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China; Department of Endocrine, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214125, China.
Department of Anesthesiology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214125, China.
J Adv Res. 2023 Sep;51:161-179. doi: 10.1016/j.jare.2022.10.014. Epub 2022 Nov 9.
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.
We aimed to elucidate the potential roles of Metrnl in DCM.
Gain- andloss-of-function experimentswere utilized to determine the roles of Metrnl in the pathological processes of DCM.
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.
Thus, Metrnl may be an attractive therapeutic target or regimen for treating DCM.
类流星激素（Metrnl）在骨骼肌、心脏和脂肪组织中广泛表达，对肥胖、胰岛素抵抗和炎症具有有益作用。Metrnl 被发现可预防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）中的作用尚未确定。
我们旨在阐明 Metrnl 在 DCM 中的潜在作用。
利用增益和失能实验来确定 Metrnl 在 DCM 病理过程中的作用。
我们发现，链脲佐菌素（STZ）诱导的（1 型糖尿病，T1D）小鼠和瘦素受体缺陷（db/db）（2 型糖尿病，T2D）小鼠的血浆 Metrnl 水平、心肌 Metrnl 蛋白和 mRNA 表达均显著下调。心脏特异性过表达（OE）Metrnl 可显著改善 T1D 和 T2D 小鼠的心脏损伤和功能障碍。相比之下，心脏特异性敲除（KO）Metrnl 则呈现相反的表型。平行实验中，OE Metrnl 可改善高糖（HG）诱导的原代新生大鼠心肌细胞肥大、凋亡和氧化损伤，而下调 Metrnl 则加剧了上述效应。抗体诱导的 Metrnl 阻断消除了 Metrnl 在体外和体内的作用。机制上，Metrnl 通过 LKB1/AMPK/ULK1 依赖性机制激活自噬途径并抑制 cGAS/STING 信号通路，在心肌细胞中，Metrnl 诱导的 ULK1 磷酸化促进了 STING 的去磷酸化和线粒体易位，使其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。
因此，Metrnl 可能是治疗 DCM 的一个有吸引力的治疗靶点或方案。
