Molecular basis for the improvement in muscle metaboreflex and mechanoreflex control in exercise-trained humans with chronic heart failure

Abstract

Previous studies have demonstrated that muscle mechanoreflex and metaboreflex controls are altered in heart failure (HF), which seems to be due to changes in cyclooxygenase (COX) pathway and changes in receptors on afferent neurons, including transient receptor potential vanilloid type-1 (TRPV1) and cannabinoid receptor type-1 (CB1). The purpose of the present study was to test the hypotheses: 1) exercise training (ET) alters the muscle metaboreflex and mechanoreflex control of muscle sympathetic nerve activity (MSNA) in HF patients. 2) The alteration in metaboreflex control is accompanied by increased expression of TRPV1 and CB1 receptors in skeletal muscle. 3) The alteration in mechanoreflex control is accompanied by COX-2 pathway in skeletal muscle. Thirty-four consecutive HF patients with ejection fractions <40% were randomized to untrained (n = 17; 54 ± 2 yr) or exercise-trained (n = 17; 56 ± 2 yr) groups. MSNA was recorded by microneurography. Mechanoreceptors were activated by passive exercise and metaboreceptors by postexercise circulatory arrest (PECA). COX-2 pathway, TRPV1, and CB1 receptors were measured in muscle biopsies. Following ET, resting MSNA was decreased compared with untrained group. During PECA (metaboreflex), MSNA responses were increased, which was accompanied by the expression of TRPV1 and CB1 receptors. During passive exercise (mechanoreflex), MSNA responses were decreased, which was accompanied by decreased expression of COX-2, prostaglandin-E2 receptor-4, and thromboxane-A2 receptor and by decreased in muscle inflammation, as indicated by increased miRNA-146 levels and the stable NF-κB/IκB-α ratio. In conclusion, ET alters muscle metaboreflex and mechanoreflex control of MSNA in HF patients. This alteration with ET is accompanied by alteration in TRPV1 and CB1 expression and COX-2 pathway and inflammation in skeletal muscle.

Keywords: exercise training; heart failure; mechanoreflex; metaboreflex; muscle sympathetic nervous system.

Fig. 1.

Experimental protocol. PE, passive exercise; IE, isometric exercise; PECA, postexercise regional circulatory arrest.

Fig. 2.

Peak of 30% isometric leg exercise in untrained and exercise-trained heart failure patients. A: muscle sympathetic nerve activity (MSNA) total activity (a.u.). B: MSNA frequency (bursts/min). C: MSNA incidence [bursts/100 heartbeats (HB)]. *P < 0.05 vs. pre within group. †P < 0.05 vs. untrained. ‡P < 0.05 vs. rest.

Fig. 3.

Sympathetic neurograms of untrained and exercise-trained heart failure patients during metaboreceptors stimulation (A) and during mechanoreceptors stimulation (B).

Fig. 4.

Metaboreflex control of MSNA assessed by %changes between the 1st minute of postexercise regional circulatory arrest and rest period in untrained (n = 17) and exercise-trained (n = 16) heart failure patients. A: delta changes in MSNA total activity (a.u.). B: frequency (bursts/min). C: incidence (bursts/100 HB). Mechanoreflex control of MSNA assessed by difference between the peak of passive exercise and rest period in untrained (n = 17) and exercise-trained (n = 16) heart failure patients. D: delta changes in MSNA total activity (a.u.). E: frequency (bursts/min). F: incidence (bursts/100 HB). Exercise training markedly increased the MSNA responses during metaboreceptors stimulation in heart failure patients. In contrast, exercise training significantly decreased MSNA responses during mechanoreceptors stimulation. Values are mean individual response. *P < 0.05 vs. pre within group. †P < 0.05 vs. untrained.

Fig. 5.

Gene expression of transient receptor potential vanilloid type-1 (TRPV1; A) and cannabinoid receptor type-1 (CB1; B) receptors in vastus lateralis in untrained (n = 11) and exercise-trained (n = 12) heart failure patients. Exercise training significantly increased gene expression of TRPV1 and CB1 receptors. Values are means ± SE. *P < 0.05 vs. pre within group. †P < 0.05 vs. untrained.

Fig. 6.

Gene expression of cyclooxygenase (COX)-1 (A) and COX-2 (B) in vastus lateralis in untrained (n = 11) and exercise-trained (n = 12) heart failure patients. C: representative Western blots (top) and densitometric analysis (bottom) of COX-2 protein expression in untrained (n = 9) and exercise-trained (n = 9) patients. Sarcomeric actin protein expression was used as internal control. Exercise training significantly decreased gene and protein expression of COX-2. Values are means ± SE. *P < 0.05 vs. pre within group. †P < 0.05 vs. untrained.

Fig. 7.

Expression of miRNA-16 (A), miRNA-143 (B), and miRNA-146 (C) in vastus lateralis in untrained (n = 11) and exercise-trained (n = 12) heart failure patients. D: representative Western blots (top) and densitometric analysis (bottom) of protein expression of NF-κB/IκB-α ratio in vastus lateralis in untrained (n = 7) and exercise-trained (n = 7) patients. Exercise training significantly increased expression of miRNA-146 and prevented the increase in protein expression of NF-κB/IκB-α ratio. Values are means ± SE. *P < 0.05 vs. pre within group. †P < 0.05 vs. untrained.