ABC | Volume 110, Nº3, March 2018

Original Article Rodrigues et al Aerobic exercise training in β 1ARKO mice Arq Bras Cardiol. 2018; 110(3):256-262 We observed that trained mice (WTt and β 1 ARKOt) showed longer total running distance than their respective controls (WTc and β 1 ARKOc). This MCAE-induced increase may be associated with cardiovascular adaptations, which are known features of aerobic exercise training. 27 Previous studies using the same aerobic exercise training protocol also observed increased exercise capacity in trained animals. 8,17 Specifically, the β 1 ARKO groups showed longer total running distance than the WT groups. It is known that sympathetic activation during aerobic exercise promotes glycogenolysis by β -AR pathway. 28,29 Probably, the β 1 ARKO mice have compensatory mechanisms in the skeletal muscle, such as modified β 2 and α 1 adrenergic signaling pathways, which could improve glycogenolysis, gluconeogenesis, insulin-independent glucose uptake and lipolysis in the skeletal muscles. 30 These compensatory mechanisms may have led to increased exercise performance in β 1 ARKO mice. However, inasmuch as this issue is not the focus of this study, further investigations are needed to test the hypothesis that β 1 ARKO mice increase exercise performance by altering β 2 and α 1 adrenergic signaling pathways. Although myocytes from β 1 ARKO mice had a higher amplitude of shortening than cells from WT mice, an independent factor effect, LV myocytes from β 1 ARKOc and WTc groups had similar contractile properties. Although β 1 AR is the predominant adrenergic receptor subtype expressed in the heart in terms of density and modulation of cardiac contraction, 31,32 its deletion had little impact on resting cardiac function, but had significant effects on cardiac function after β -agonist stimulation. 33 Other studies did not observe changes in cardiomyocyte contractility upon loss of β 1 -AR 34 or β 1/2 -AR under basal conditions. 35 Therefore, the similarity between β 1 ARKOc and WTc groups suggests that β 1 -AR has little impact on the contractile properties of cardiomyocytes under basal conditions. More important, the MCAE program increased the amplitude of shortening of LV myocytes from β 1 ARKO mice. The MCAE may have triggered two compensatory mechanisms in the heart of β 1 ARKO mice. First, an increase in α 1 -ARs signaling is common under situations of β 1 -ARs desensitization when the reduction of β 1 -adrenergic signaling is compensated by an increase in α 1 -adrenergic signaling pathway, which could help preserve cardiac function. 36 Although not evaluated here, an increased inotropic responsiveness of rat cardiomyocytes via α 1 -AR stimulation was found as an adaptation to aerobic exercise training. 37,38 Moreover, the potential therapeutic role of α 1 -ARs to maintain normal cardiac function, especially in terms of commitment of the β 1 -adrenergic signaling pathway, has been proposed in previous studies. 37-40 Second, MCAE may have reduced the responsiveness of β 2 -AR in myocytes of β 1 ARKO mice. When β 2 -AR coupling to G i protein is reduced, the inhibitory effect of the receptor to adenylate cyclase activation is also reduced, 5 which causes an increased cAMP production and phosphorylation of proteins involved in cardiomyocyte excitation-contraction coupling. 6 The time courses of β 1 ARKO LV myocyte contraction and relaxation were also improved by MCAE, indicating enhanced systolic and diastolic functions. The Ca 2+ regulatory proteins modulate cardiomyocyte mechanical properties. While faster myocyte contraction is associated with increased density and or activity of L-type Ca 2+ channels and RyR 2 , quicker relaxation is dependent on the increased activity and or density of SERCA2a, PLB and NCX. 6 Although not measured in the present study, MCAE may have improved the net balance of cardiac Ca 2+ handling proteins in β 1 ARKO mice. Such adaptations have been demonstrated previously in a different model for sympathetic hyperactivity. 8,16 In addition, endurance-exercise training may have reduced the β / α -MHC ratio, 20 which would also help explain the increased velocities of LV myocyte contraction and relaxation. In recent years, high-intensity interval training (HIIT) has emerged as the method that leads to significant benefits to cardiac function. For instance, mice submitted to HIIT Figure 2 – Cell contractility. A) Shortening. B) Velocity of shortening. C) Velocity of relaxation. WTc, wild-type control (n = 7; N = 14-39 cells from each mouse); WTt, wild-type trained (n = 6; N = 8-27 cells from each mouse); β1ARKOc, knockout β1-AR control (n = 7; N = 24-31 cells from each mouse); β1ARKOt, knockout β1-AR trained (n = 6; N = 17-29 cells from each mouse). Values are means ± SD.*p < 0.05 vs. WTc group; §p < 0.05 vs. WTt group; #p < 0.05 vs. β1ARKOc group. 3.5 3.0 2.5 2.0 1.5 0 shortening (% r.c.l.) * * #§ § A B 240 210 180 150 120 0 Time to peak (ms) C 140 120 100 80 60 0 WTc WTt B1c B1t Time to 50% (ms) 259