Sex Differences in Cardiac AMP-Activated Protein Kinase Following Exhaustive Exercise

Abstract

Ischemic heart disease presents with significant differences between sexes. Endurance exercise protects the heart against ischemic disease and also distinctly impacts male and female patients through unidentified mechanisms, though some evidence implicates 5'-AMP-activated protein kinase (AMPK). The purpose of this investigation was to assess the impact of training and sex on cardiac AMPK activation following exhaustive exercise. AMPK activation was measured in trained and sedentary mice of both sexes. Trained mice ran on a treadmill at progressively increasing speeds and duration for 12 weeks. Trained and sedentary mice of both sexes were euthanized immediately following exhaustive exercise and compared to sedentary controls. Endurance training elicited adaptations indicative of aerobic adaptation including higher max running velocities and cardiac hypertrophy with no differences between males and females. AMPK activity was higher in male compared to females, and trained exhibited higher AMPK activity compared to sedentary mice. In response to training, male mice activated AMPK more robustly than female mice. Chronic exercise training increases the ability to activate cardiac AMPK in response to exhaustive exercise in a sex-specific manner. Understanding the interaction between exercise and sex is vital for use of exercise as medicine for heart disease in both men and women.

Keywords: AMPK; cardiac; exercise; sex differences.

Fig. 1

Training and exhaustive exercise bout protocols. a Summary of 12-week training protocol. b Summary of exhaustion protocol for trained (TR) and sedentary (SED) exhausted mice.

Fig. 2

Training adaptations and cardiac morphometrics for male and female trained (TR) and sedentary (SED) rest and exhausted mice. a Body weight changes in male and female mice. b Heart weight in male and female mice. c Heart/body weight. d Max running speed. e Heart weight normalized to training (max running speed). Data were analyzed by a 2-way ANOVA with sex and training as independent variables. n=20 TR-Exhausted (10 male, 10 female); n=18 SED-Exhausted (9 male, 9 female); and n=10 SED-Rest (5 male, 5 female). *p<0.05 effect of training, ^p<0.05 significant effect of sex. Data are presented as means±SEM.

Fig. 3

Left ventricular AMPK activation in trained-exhausted (TR-Exhausted), sedentary-exhausted (SED-Exhausted), and sedentary-resting (SED-Rest) groups for both male and female mice. a LV AMPK activity. n=20 TR-Exhausted (10 male, 10 female); SED-Exhausted (8 male, 8 female); SED-Rest (5 male, 5 female). *p<0.05 significant effect of training, ^p<0.05 significant effect of sex, #significant difference within sex. b LV AMPK protein expression with representative image. n=20 TR-Exhausted (6 male, 6 female), SED-Exhausted (4 male, 4 female), SED-Rest (4 male, 4 female). *p<0.05 significant effect of training, ^p<0.05 significant effect of sex, #significant difference within sex. Data were analyzed by 2-way ANOVA (sex × training) with post hoc analyses. Data are presented as means±SEM.

Fig. 4

Linear association between cardiac AMPK activity and indicators of aerobic training in male and female mice. a Heart weight normalized to body weight and max running speed. b AMPK activity and max running speed. c AMPK activity and heart weight normalized to body weight. Data were analyzed by multiple linear regressions. n=20 TR-Exhausted (10 male, 10 female); n=18 SED-Exhausted (9 male, 9 female); and n=10 SED-Rest (5 male, 5 female).