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Theranostics 2024; 14(5):2246-2264. doi:10.7150/thno.93192 This issue Cite

Research Paper

Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit

Wenlin Yuan1, Hui Lin2,3, Yuan Sun2,5, Lihuan Liu1, Meijuan Yan1, Yujuan Song1, Xiaofan Zhang1, Xiangling Lu1, Yipei Xu1, Qiyue He1, Kunfu Ouyang6, Chenglin Zhang1, Yong Pan1, Yu Huang7, Ying Li1✉, Xifeng Lu1,2,3,4✉, Jie Liu1✉

1. Department of pathophysiology, Shenzhen University Medical School, Shenzhen University, Shenzhen, China.
2. Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
3. Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
4. Department of Pharmacology, Shantou University Medical College, Shantou, China.
5. Department of Pharmacology, College of Pharmacy, Shenzhen Technology University, Shenzhen, China.
6. Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen, China.
7. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.

✉ Corresponding authors: Jie Liu, M.D., Ph.D., Tel: +86-755-22673500, Email: liujedu.cn; Xifeng Lu, Ph.D., Email: xifengluedu.cn; Ying Li, Ph.D., Email: liying826edu.cn.

Citation:
Yuan W, Lin H, Sun Y, Liu L, Yan M, Song Y, Zhang X, Lu X, Xu Y, He Q, Ouyang K, Zhang C, Pan Y, Huang Y, Li Y, Lu X, Liu J. Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit. Theranostics 2024; 14(5):2246-2264. doi:10.7150/thno.93192. https://www.thno.org/v14p2246.htm
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Abstract

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Aim: Adipose tissue (AT) dysfunction that occurs in both obesity and lipodystrophy is associated with the development of cardiomyopathy. However, it is unclear how dysfunctional AT induces cardiomyopathy due to limited animal models available. We have identified vacuolar H+-ATPase subunit Vod1, encoded by Atp6v0d1, as a master regulator of adipogenesis, and adipose-specific deletion of Atp6v0d1 (Atp6v0d1AKO) in mice caused generalized lipodystrophy and spontaneous cardiomyopathy. Using this unique animal model, we explore the mechanism(s) underlying lipodystrophy-related cardiomyopathy.

Methods and Results: Atp6v0d1AKO mice developed cardiac hypertrophy at 12 weeks, and progressed to heart failure at 28 weeks. The Atp6v0d1AKO mouse hearts exhibited excessive lipid accumulation and altered lipid and glucose metabolism, which are typical for obesity- and diabetes-related cardiomyopathy. The Atp6v0d1AKO mice developed cardiac insulin resistance evidenced by decreased IRS-1/2 expression in hearts. Meanwhile, the expression of forkhead box O1 (FoxO1), a transcription factor which plays critical roles in regulating cardiac lipid and glucose metabolism, was increased. RNA-seq data and molecular biological assays demonstrated reduced expression of myocardin, a transcription coactivator, in Atp6v0d1AKO mouse hearts. RNA interference (RNAi), luciferase reporter and ChIP-qPCR assays revealed the critical role of myocardin in regulating IRS-1 transcription through the CArG-like element in IRS-1 promoter. Reducing IRS-1 expression with RNAi increased FoxO1 expression, while increasing IRS-1 expression reversed myocardin downregulation-induced FoxO1 upregulation in cardiomyocytes. In vivo, restoring myocardin expression specifically in Atp6v0d1AKO cardiomyocytes increased IRS-1, but decreased FoxO1 expression. As a result, the abnormal expressions of metabolic genes in Atp6v0d1AKO hearts were reversed, and cardiac dysfunctions were ameliorated. Myocardin expression was also reduced in high fat diet-induced diabetic cardiomyopathy and palmitic acid-treated cardiomyocytes. Moreover, increasing systemic insulin resistance with rosiglitazone restored cardiac myocardin expression and improved cardiac functions in Atp6v0d1AKO mice.

Conclusion: Atp6v0d1AKO mice are a novel animal model for studying lipodystrophy- or metabolic dysfunction-related cardiomyopathy. Moreover, myocardin serves as a key regulator of cardiac insulin sensitivity and metabolic homeostasis, highlighting myocardin as a potential therapeutic target for treating lipodystrophy- and diabetes-related cardiomyopathy.

Citation styles

APA
Yuan, W., Lin, H., Sun, Y., Liu, L., Yan, M., Song, Y., Zhang, X., Lu, X., Xu, Y., He, Q., Ouyang, K., Zhang, C., Pan, Y., Huang, Y., Li, Y., Lu, X., Liu, J. (2024). Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit. Theranostics, 14(5), 2246-2264. https://doi.org/10.7150/thno.93192.

ACS
Yuan, W.; Lin, H.; Sun, Y.; Liu, L.; Yan, M.; Song, Y.; Zhang, X.; Lu, X.; Xu, Y.; He, Q.; Ouyang, K.; Zhang, C.; Pan, Y.; Huang, Y.; Li, Y.; Lu, X.; Liu, J. Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit. Theranostics 2024, 14 (5), 2246-2264. DOI: 10.7150/thno.93192.

NLM
Yuan W, Lin H, Sun Y, Liu L, Yan M, Song Y, Zhang X, Lu X, Xu Y, He Q, Ouyang K, Zhang C, Pan Y, Huang Y, Li Y, Lu X, Liu J. Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit. Theranostics 2024; 14(5):2246-2264. doi:10.7150/thno.93192. https://www.thno.org/v14p2246.htm

CSE
Yuan W, Lin H, Sun Y, Liu L, Yan M, Song Y, Zhang X, Lu X, Xu Y, He Q, Ouyang K, Zhang C, Pan Y, Huang Y, Li Y, Lu X, Liu J. 2024. Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit. Theranostics. 14(5):2246-2264.

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