Korean J Physiol Pharmacol.  2022 Sep;26(5):313-323. 10.4196/kjpp.2022.26.5.313.

Protective effect of low-intensity treadmill exercise against acetylcholine-calcium chloride-induced atrial fibrillation in mice

• Sung DJ
• Jeon YK
• Choi J
• Kim B
• Golpasandi S
• Park SW
• Oh SB
• Bae YM

• KMID: 2532761
• DOI: http://doi.org/10.4196/kjpp.2022.26.5.313

Abstract

Atrial fibrillation (AF) is the most common supraventricular arrhythmia, and it corresponds highly with exercise intensity. Here, we induced AF in mice using acetylcholine (ACh)-CaCl₂ for 7 days and aimed to determine the appropriate exercise intensity (no, low, moderate, high) to protect against AF by running the mice at different intensities for 4 weeks before the AF induction by ACh-CaCl₂ . We examined the AF-induced atrial remodeling using electrocardiogram, patch-clamp, and immunohistochemistry. After the AF induction, heart rate, % increase of heart rate, and heart weight/body weight ratio were significantly higher in all the four AF groups than in the normal control; highest in the high-ex AF and lowest in the low-ex (lower than the no-ex AF), which indicates that low-ex treated the AF. Consistent with these changes, G protein-gated inwardly rectifying K + currents, which were induced by ACh, increased in an exercise intensity-dependent manner and were lower in the low-ex AF than the no-ex AF. The peak level of Ca²⁺ current (at 0 mV) increased also in an exercise intensity-dependent manner and the inactivation time constants were shorter in all AF groups except for the low-ex AF group, in which the time constant was similar to that of the control. Finally, action potential duration was shorter in all the four AF groups than in the normal control; shortest in the high-ex AF and longest in the low-ex AF. Taken together, we conclude that low-intensity exercise protects the heart from AF, whereas high-intensity exercise might exacerbate AF.

Keyword

Acetylcholine-calcium chloride; Action potential; Atrial fibrillation; Exercise-intensity; GIRK channels

Figure

• 

  Fig. 1 Effects of treadmill exercise on atrial fibrillation-like arrhythmogenesis induced by ACh + CaCl2. (A) Representative electrocardiogram recorded from mice after intravenous (IV) treatment of ACh + CaCl2 (for 7 days) in control and atrial fibrillation (AF) exercise groups. (B) Heart rates of the groups. (C) Percent (%) increase in heart rates of the groups. n = 25.

• 

  Fig. 2 Morphological changes in mouse atrium for control and atrial fibrillation (AF) exercise groups. (A) Toluidine blue staining shows fibrotic tissues (blue). (B) Normalization of heart weight (g) to body weight (g) for comparison between groups. (C) Comparison of single cell size (pF) between groups. N.S., not significant. n = 25.

• 

  Fig. 3 Inward rectifier and voltage-gated K+ currents in atrial myocytes. These two K+ currents were briefly examined by the hyperpolarizing and depolarizing voltage steps from the holding potential of –70 mV (figure inset). (A) Representative recordings of the K+ currents in atrial myocytes that were enzymatically dispersed from the heart. (B) K+ current-voltage (I–V) relationships (n = 5). AF, atrial fibrillation.

• 

  Fig. 4 GIRK currents activity in atrial myocytes. (A) Representative recordings of GIRK currents induced by ACh (100 µM). (B) Representative current-voltage relationships. (C) Time for GIRK currents to decline to 10% of the peaks (T90). An arrow in A indicates a persistent GIRK currents in the high-ex AF group after Ach was washed out. GIRK, G-protein activated inwardly rectifying K+; AF, atrial fibrillation. n = 8.

• 

  Fig. 5 L-type Ca2+ currents in atrial myocytes. (A) Representative recordings of L-type Ca2+ currents. (B) Current-voltage (I–V) relationships. (C) Peak currents at 0 mV. (D) Inactivation time constants (τ) of the groups (fit with a single exponential function). AF, atrial fibrillation. n = 5. ***p < 0.001.

• 

  Fig. 6 Action potential durations in atrial myocytes. (A) Representative action potentials. (B) APD90 of the groups. (C) Resting membrane potentials of the groups. APD90, action potential duration 90%; AF, atrial fibrillation; N.S., not significant. n = 8.

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