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Background <p>Intense or exhaustive exercise is known to increase the risk of ventricular arrhythmias. One important mechanism is the disruption of intracellular calcium homeostasis. Exercise preconditioning (EP) has been reported to exert cardioprotective effects. However, under exercise-induced stress, how EP reduces arrhythmia susceptibility through regulation of calcium-handling signaling pathways remains unclear. This study aimed to investigate whether EP reduces exercise-induced arrhythmias by modulating the CaMKII–RyR2–PLN signaling pathway.</p> Results <p>In this study, a rat model of repeated exhaustive exercise (EE) was established. The effects of EE and EP on myocardial electrophysiological properties were compared. The results showed that EE significantly shortened exhaustion time. EE also increased the incidence of electrically induced ventricular arrhythmias. In addition, EE markedly altered the expression of proteins related to calcium homeostasis. Specifically, EE significantly increased CaMKII activation and enhanced RyR2 phosphorylation at the Ser2814 site. These changes were accompanied by reduced SERCA2a expression and elevated PP1 levels. These findings indicated impaired sarcoplasmic reticulum calcium reuptake and increased calcium leakage. EP significantly prolonged exhaustion time and preserved myocardial structural integrity. EP reduced the occurrence of ventricular arrhythmias. Moreover, EP suppressed CaMKII activity and prevented excessive RyR2 phosphorylation. SERCA2a expression was restored, and PP1 levels were partially normalized. The CaMKII inhibitor KN-93 acted synergistically with EP. This result further confirmed the central role of CaMKII overactivation in exercise-induced ventricular arrhythmias.</p> Conclusion <p>EP effectively reduced susceptibility to exercise-induced ventricular arrhythmias by regulating the CaMKII–RyR2–PLN signaling pathway and maintaining calcium homeostasis. These findings highlight CaMKII as a potential therapeutic target. In addition, they provide mechanistic evidence for the cardioprotective effects of exercise preconditioning under extreme exercise stress.</p>

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Exercise preconditioning reduces the electrostimulation-induced incidence of arrhythmias in exhausted rats by regulating the CaMKⅡ-RyR2 signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Yibo Wang,
  • Yang Wang,
  • Peng Xu,
  • Chenyan Wang,
  • Heling Huang,
  • Xiangnong Li,
  • Huanhuan Huang,
  • Xiaoli Zhang,
  • Xuebin Cao

摘要

Background

Intense or exhaustive exercise is known to increase the risk of ventricular arrhythmias. One important mechanism is the disruption of intracellular calcium homeostasis. Exercise preconditioning (EP) has been reported to exert cardioprotective effects. However, under exercise-induced stress, how EP reduces arrhythmia susceptibility through regulation of calcium-handling signaling pathways remains unclear. This study aimed to investigate whether EP reduces exercise-induced arrhythmias by modulating the CaMKII–RyR2–PLN signaling pathway.

Results

In this study, a rat model of repeated exhaustive exercise (EE) was established. The effects of EE and EP on myocardial electrophysiological properties were compared. The results showed that EE significantly shortened exhaustion time. EE also increased the incidence of electrically induced ventricular arrhythmias. In addition, EE markedly altered the expression of proteins related to calcium homeostasis. Specifically, EE significantly increased CaMKII activation and enhanced RyR2 phosphorylation at the Ser2814 site. These changes were accompanied by reduced SERCA2a expression and elevated PP1 levels. These findings indicated impaired sarcoplasmic reticulum calcium reuptake and increased calcium leakage. EP significantly prolonged exhaustion time and preserved myocardial structural integrity. EP reduced the occurrence of ventricular arrhythmias. Moreover, EP suppressed CaMKII activity and prevented excessive RyR2 phosphorylation. SERCA2a expression was restored, and PP1 levels were partially normalized. The CaMKII inhibitor KN-93 acted synergistically with EP. This result further confirmed the central role of CaMKII overactivation in exercise-induced ventricular arrhythmias.

Conclusion

EP effectively reduced susceptibility to exercise-induced ventricular arrhythmias by regulating the CaMKII–RyR2–PLN signaling pathway and maintaining calcium homeostasis. These findings highlight CaMKII as a potential therapeutic target. In addition, they provide mechanistic evidence for the cardioprotective effects of exercise preconditioning under extreme exercise stress.