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Semaglutide administration protects cardiomyocytes in db/db mice via energetic improvement and mitochondrial quality control

Acta Pharmacologica Sinica volume 46, pages 1250–1261 (2025)Cite this article

Abstract

Diabetic cardiomyopathy causes end-stage heart failure, resulting in high morbidity and mortality in type 2 diabetes mellitus (T2DM) patients. Long-term treatment targeting metabolism is an emerging field in the treatment of diabetic cardiomyopathy. Semaglutide, an agonist of the glucagon-like peptide 1 receptor, is clinically approved for the treatment of T2DM and provides cardiac benefits in patients. However, the cardioprotective mechanism of semaglutide, especially its direct effects on cardiomyocytes (CMs), is not fully understood. Here, we used 8-week diabetic and obese db/db mice treated with semaglutide (200 μg·kg·d−1, i.p.) to study its direct effect on CMs and the underlying mechanisms. Our results revealed that the consecutive application of semaglutide improved cardiac function. Increased AMPK and ULK1 phosphorylation levels were detected, accompanied by elevated [Ca2+]mito. Seahorse analysis revealed that semaglutide increases ATP production via elevated basal and maximum respiration rates as well as spare respiration capacity in CMs. Transmission electron microscopy revealed improved mitochondrial morphology in the cardiomyocytes of db/db mice. On the other hand, Western blot analysis revealed increased Parkin and LC3 protein expression, indicating mitophagy in CMs. Collectively, our findings demonstrate that semaglutide directly protects CMs from high-glucose damage by promoting AMPK-dependent ATP production as well as ULK1-mediated mitophagy in db/db mice.

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Fig. 1: Phenotype changes in db/db mice treated with semaglutide.
Fig. 2: Semaglutide improves cardiac function in db/db mice.
Fig. 3: Mitochondrial function is improved in db/db mice treated with semaglutide.
Fig. 4: Semaglutide treatment improves mitochondrial morphology in the cardiomyocytes of db/db mice.
Fig. 5: RNA sequencing analysis of cardiomyocytes from db/db mice and semaglutide treated db/db mice.
Fig. 6: Elevated mitochondrial Ca2+ uptake after semaglutide treatment in db/db mice.
Fig. 7: Semaglutide induces mitophagy to improve cardiac function in db/db mice.
Fig. 8: Schematic diagram of the mechanism by which semaglutide protects cardiomyocytes in db/db mice.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China 82121001 (YJ), 32200973 (SL), 82270393 (SL), and the Natural Science Foundation of Jiangsu Province BK20220310 (SL).

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Author notes

  1. These authors contributed equally: Meng-yun Tian, Ji-qin Yang

Authors and Affiliations

  1. Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China

    Meng-yun Tian, Ji-qin Yang, Jin-chuan Hu, Shan Lu & Yong Ji

  2. State Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, 150081, China

    Yong Ji

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  1. Meng-yun Tian
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Contributions

Conceptualization, SL, YJ and MYT; methodology, JCH, MYT and JQY; software, MYT; validation, SL, YJ, MYT and JQY; formal analysis, MYT; investigation, SL, YJ, MYT, JCH and JQY; resources, SL, YJ, MYT, and JQY; writing-original draft, MYT; writing-review & editing, SL and YJ; visualization, MYT, SL and YJ; supervision, SL and YJ; project administration, SL and YJ; funding acquisition, SL and YJ.

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Correspondence to Shan Lu or Yong Ji.

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Tian, My., Yang, Jq., Hu, Jc. et al. Semaglutide administration protects cardiomyocytes in db/db mice via energetic improvement and mitochondrial quality control. Acta Pharmacol Sin 46, 1250–1261 (2025). https://doi.org/10.1038/s41401-024-01448-9

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