Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy
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 di...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Journal of Advanced Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123222002430 |
| _version_ | 1797729970844336128 |
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| author | Qing-Bo Lu Yi Ding Yao Liu Zi-Chao Wang Yu-Jie Wu Kai-Ming Niu Ke-Xue Li Ji-Ru Zhang Hai-Jian Sun |
| author_facet | Qing-Bo Lu Yi Ding Yao Liu Zi-Chao Wang Yu-Jie Wu Kai-Ming Niu Ke-Xue Li Ji-Ru Zhang Hai-Jian Sun |
| author_sort | Qing-Bo Lu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T11:37:19Z |
| format | Article |
| id | doaj.art-4eb865f02ab74d7bb0bdb2206bf165b1 |
| institution | Directory Open Access Journal |
| issn | 2090-1232 |
| language | English |
| last_indexed | 2024-03-12T11:37:19Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj.art-4eb865f02ab74d7bb0bdb2206bf165b12023-09-01T05:01:01ZengElsevierJournal of Advanced Research2090-12322023-09-0151161179Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagyQing-Bo Lu0Yi Ding1Yao Liu2Zi-Chao Wang3Yu-Jie Wu4Kai-Ming Niu5Ke-Xue Li6Ji-Ru Zhang7Hai-Jian Sun8Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China; Department of Endocrine, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214125, ChinaDepartment of Anesthesiology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214125, ChinaDepartment of Cardiac Ultrasound, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, ChinaDepartment of Physiology, Xuzhou Medical University, Xuzhou 221004, China; Corresponding authors at: State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore. Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China (Hai-Jian Sun). Department of Anesthesiology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, 214125, China (Ji-Ru Zhang). Department of Physiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China (Ke-Xue Li).Department of Anesthesiology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi 214125, China; Corresponding authors at: State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore. Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China (Hai-Jian Sun). Department of Anesthesiology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, 214125, China (Ji-Ru Zhang). Department of Physiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China (Ke-Xue Li).Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore, Singapore; Corresponding authors at: State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore. Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China (Hai-Jian Sun). Department of Anesthesiology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, 214125, China (Ji-Ru Zhang). Department of Physiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China (Ke-Xue Li).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.http://www.sciencedirect.com/science/article/pii/S2090123222002430DiabetesCardiomyopathyMetrnlAMPKAutophagySTING |
| spellingShingle | Qing-Bo Lu Yi Ding Yao Liu Zi-Chao Wang Yu-Jie Wu Kai-Ming Niu Ke-Xue Li Ji-Ru Zhang Hai-Jian Sun Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy Journal of Advanced Research Diabetes Cardiomyopathy Metrnl AMPK Autophagy STING |
| title | Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy |
| title_full | Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy |
| title_fullStr | Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy |
| title_full_unstemmed | Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy |
| title_short | Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy |
| title_sort | metrnl ameliorates diabetic cardiomyopathy via inactivation of cgas sting signaling dependent on lkb1 ampk ulk1 mediated autophagy |
| topic | Diabetes Cardiomyopathy Metrnl AMPK Autophagy STING |
| url | http://www.sciencedirect.com/science/article/pii/S2090123222002430 |
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