Obesity increased cardiomyocyte calcium transients and systolic sarcomere shortening, which were normalized by treatment with semaglutide.
High-fat diets elevated calcium levels and contraction strength in heart cells compared to control diets.
Semaglutide treatment reversed the effects of high-fat diets on calcium transients and sarcomere shortening.
Caffeine-induced calcium release and L-type calcium channel activity were reduced with semaglutide treatment.
Switching to a low-fat diet further increased calcium transients and sarcomere shortening despite similar weight.
The findings suggest potential mechanisms for the differing effects of GLP-1 receptor agonists in obesity-related heart conditions.
Simplified
AIMS: Obesity increases the risk of heart failure with preserved (), but not reduced ejection fraction (). The glucagon-like peptide-1 receptor agonist (GLP-1-RA) semaglutide improves outcome of patients with obesity with or without HFpEF, while GLP-1-RAs were associated with adverse outcome in patients with HFrEF. Here, we investigate the effect of in vivo treatment with semaglutide on excitation-contraction coupling in a rat model of obesity.
METHODS AND RESULTS: Rats received high-fat/high-fructose diet for 8 weeks and were then randomized to semaglutide (HFD/Sema) or vehicle (HFD/Veh) for another 8 weeks, during which they could choose between HFD and a low-fat/high-fructose diet (LFD). Control rats received either standard chow (CON), HFD or LFD only, without treatment. After 16 weeks, sarcomere shortening and cytosolic Caconcentrations ([Ca]) were determined in isolated cardiomyocytes. Compared with CON, HFD/Veh increased the amplitude of [Ca]transients and systolic sarcomere shortening in absence or presence of β-adrenergic stimulation, which was reversed by HFD/Sema. Caffeine-induced sarcoplasmic reticulum (SR) Carelease and L-type Cachannel (LTCC) currents were reduced by HFD/Sema versus HFD/Veh, while SR CaATPase activity remained unaffected. Compared with HFD, LFD increased [Ca]transients and sarcomere shortening further despite similar effects on body weight. 2+ 2+ 2+ 2+ 2+ 2+ 2+ c c c
CONCLUSIONS: While HFD increased cardiomyocyte [Ca]transients and systolic sarcomere shortening, semaglutide normalized these alterations, mediated by reduced SR Caload and LTCC currents. Because increased LTCC currents were previously traced to cardiac hypertrophy, these effects may explain why GLP-1-RAs provide benefits for patients with obesity with or without HFpEF, but rather adverse outcome in HFrEF. 2+ 2+ c
Key numbers
11.6 ± 2%
Body Weight Loss
Weight loss in group compared to after 8 weeks.
Higher in vs.
Amplitude Increase
Comparison of calcium transients in cardiomyocytes from and groups.
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C.M. received speaker or advisory honoraria from Bristol Myers Squibb, Boehringer Ingelheim, AstraZeneca, Servier, Amgen, NovoNordisk, Bayer, Novartis, Edwards and Berlin Chemie. U.D. has received speaker honoraria of Alnylam, Recordati Rare Diseases and MSD. All other authors have declared that no conflict of interest exists.
