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

Jan 24, 2025Acta pharmacologica Sinica

Semaglutide helps heart muscle cells in diabetic mice by improving energy use and mitochondrial health

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Abstract

Semaglutide treatment improved cardiac function in diabetic db/db mice over 8 weeks.

The treatment increased levels of proteins involved in energy production and cellular repair in cardiomyocytes.
Higher phosphorylation of AMPK and ULK1 was observed, which may enhance ATP production and promote cell health.
Increases in ATP production were linked to elevated respiration rates and capacity in cardiomyocytes.
Mitochondrial morphology improved in cardiomyocytes, suggesting enhanced mitochondrial health.
Increased expression of Parkin and LC3 indicated that semaglutide may promote the removal of damaged mitochondria in cardiomyocytes.

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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, 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 [Ca]. 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. -1 2+ mito

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

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