Paradoxical SERCA dysregulation contributes to atrial fibrillation in a model of diet-induced obesity

Ponce-Balbuena, D.; Tyrrell, D.; Cruz-Cortes, C.; Guerrero-Serna, G.; Monteiro da Rocha, A.; Herron, T. J.; Song, J.; Raza, D.; Anumonwo, J.; Goldstein, D.; Espinoza-Fonseca, L. M.

doi:10.1101/2024.08.02.606385

bioRxiv · 10.1101/2024.08.02.606385

Paradoxical SERCA dysregulation contributes to atrial fibrillation in a model of diet-induced obesity

Ponce-Balbuena, D.·Tyrrell, D.·Cruz-Cortes, C.·Guerrero-Serna, G.·Monteiro da Rocha, A.·Herron, T. J.·Song, J.·Raza, D.·Anumonwo, J.·Goldstein, D.·Espinoza-Fonseca, L. M.

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Abstract

Obesity is a major risk factor for atrial fibrillation (AF) the most common serious cardiac arrhythmia, but the molecular mechanisms underlying diet-induced AF remain unclear. In this study, we subjected mice to a chronic high-fat diet and acute sympathetic activation ( two-hit model) to study the mechanisms by which diet-induced obesity promotes AF. Surface electrocardiography revealed that diet-induced obesity and sympathetic activation synergize during intracardiac tachypacing to induce AF. At the cellular level, diet-induced obesity and acute adrenergic stimulation facilitate the formation of delayed afterdepolarizations in atrial myocytes, implicating altered Ca2+ dynamics as the underlying cause of AF. We found that diet-induced obesity does not alter the expression of major Ca2+-handling proteins in atria, including the sarcoplasmic reticulum Ca2+-ATPase (SERCA), a major component of beat-to-beat Ca2+ cycling in the heart. Paradoxically, obesity reduces phospholamban phosphorylation, suggesting decreased SERCA activity, yet atrial myocytes from obese mice showed a significantly increased Ca2+ transient amplitude and SERCA-mediated Ca2+ uptake. Adrenergic stimulation further increases the Ca2+ transient amplitude but does not affect Ca2+ reuptake in atrial myocytes from obese mice. Transcriptomics analysis showed that a high-fat diet prompts upregulation of neuronatin, a protein that has been implicated in obesity and is known to stimulate SERCA activity. We propose a mechanism in which obesity primes SERCA for paradoxical activation, and adrenergic stimulation facilitates AF conversion through a Ca2+-induced Ca2+ release gain in atrial myocytes. Overall, this study links obesity, altered Ca2+ signaling, and AF, and targeting this mechanism may prove effective for treating obesity-induced AF.

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Ponce-Balbuena, D., Tyrrell, D., Cruz-Cortes, C., Guerrero-Serna, G., Monteiro da Rocha, A., Herron, T. J., Song, J., Raza, D., Anumonwo, J., Goldstein, D., Espinoza-Fonseca, L. M.. 2024-08-06. Paradoxical SERCA dysregulation contributes to atrial fibrillation in a model of diet-induced obesity. https://doi.org/10.1101/2024.08.02.606385

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