Exercise Training Enhances Angiogenesis-Related Gene Responses in Skeletal Muscle of Patients with Chronic Heart Failure

Abstract

Peripheral myopathy consists of a hallmark of heart failure (HF). Exercise enhanced skeletal muscle angiogenesis, and thus, it can be further beneficial towards the HF-induced myopathy. However, there is limited evidence regarding the exercise type that elicits optimum angiogenic responses of skeletal muscle in HF patients. This study aimed to (a) compare the effects of a high-intensity-interval-training (HIIT) or combined HIIT with strength training (COM) exercise protocol on the expression of angiogenesis-related factors in skeletal muscle of HF patients, and (b) examine the potential associations between the expression of those genes and capillarization in the trained muscles. Thirteen male patients with chronic HF (age: 51 ± 13 y; BMI: 27 ± 4 kg/m2) were randomly assigned to a 3-month exercise program that consisted of either HIIT (N = 6) or COM training (N = 7). Vastus lateralis muscle biopsies were performed pre- and post-training. RT-PCR was used to quantify the fold changes in mRNA expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR-2), hypoxia-inducible factor 1 alpha (HIF-1α), angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), angiopoietin receptor (Tie2), and matrix metallopeptidase 9 (MMP-9), and immunohistochemistry to assess capillarization in skeletal muscle post-training. There was an overall increase in the expression levels of VEGF, VEGFR-2, HIF-1α, Ang2, and MMP9 post-training, while these changes were not different among groups. Changes in capillary-to-fibre ratio were found to be strongly associated with Tie2 and HIF-1α expression. This was the first study demonstrating that both HIIT and combined HIIT with strength training enhanced similarly the expression profile of angiogenic factors in skeletal muscle of HF patients, possibly driving the angiogenic program in the trained muscles, although those gene expression increases were found to be only partially related with muscle capillarization.

Trial registration: ClinicalTrials.gov NCT02387411.

Keywords: angiogenesis; capillarization; cardiac rehabilitation; heart failure; skeletal muscle.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Box-plot diagrams showing the changes in the mRNA expression of vascular endothelial growth factor (VEGF; A), vascular endothelial growth factor receptor 2 (VEGFR-2; B), hypoxia-inducible factor 1 alpha (HIF-1α; C), angiopoietin 1 (Ang1; D), angiopoietin 2 (Ang2; E), angiopoietin receptor (Tie2; F), and matrix metallopeptidase 9 (MMP9; G) in the skeletal muscle of heart failure patients following either high-intensity-interval training (HIIT; N = 6) or combined HIIT with strength exercise training (COM; N = 7) and in the total number of patients (N = 13). * Significantly different compared to pre-exercise levels p < 0.05.

Figure 2

Associations between the fold change of Tie2 receptor expression (A) and the capillary-to-fibre ratio percentage change (%) and the absolute number of capillary-to-fibre ratio post-exercise training (B), as well as between the fold changes of HIF-1α expression and the absolute number of capillary-to-fibre ratio post-training (C) in skeletal muscles of the total number of HF patients [total N = 13; HIIT N = 6 (open cycles); and COM N = 7 (filled cycles)].