Effects of aerobic and inspiratory training on skeletal muscle microRNA-1 and downstream-associated pathways in patients with heart failure

Ligia M Antunes-Correa, Patricia F Trevizan, Aline V N Bacurau, Larissa Ferreira-Santos, João L P Gomes, Ursula Urias, Patricia A Oliveira, Maria Janieire N N Alves, Dirceu R de Almeida, Patricia C Brum, Edilamar M Oliveira, Ludhmila Hajjar, Roberto Kalil Filho, Carlos Eduardo Negrão, Ligia M Antunes-Correa, Patricia F Trevizan, Aline V N Bacurau, Larissa Ferreira-Santos, João L P Gomes, Ursula Urias, Patricia A Oliveira, Maria Janieire N N Alves, Dirceu R de Almeida, Patricia C Brum, Edilamar M Oliveira, Ludhmila Hajjar, Roberto Kalil Filho, Carlos Eduardo Negrão

Abstract

Background: The exercise intolerance in chronic heart failure with reduced ejection fraction (HFrEF) is mostly attributed to alterations in skeletal muscle. However, the mechanisms underlying the skeletal myopathy in patients with HFrEF are not completely understood. We hypothesized that (i) aerobic exercise training (AET) and inspiratory muscle training (IMT) would change skeletal muscle microRNA-1 expression and downstream-associated pathways in patients with HFrEF and (ii) AET and IMT would increase leg blood flow (LBF), functional capacity, and quality of life in these patients.

Methods: Patients age 35 to 70 years, left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association functional classes II-III, were randomized into control, IMT, and AET groups. Skeletal muscle changes were examined by vastus lateralis biopsy. LBF was measured by venous occlusion plethysmography, functional capacity by cardiopulmonary exercise test, and quality of life by Minnesota Living with Heart Failure Questionnaire. All patients were evaluated at baseline and after 4 months.

Results: Thirty-three patients finished the study protocol: control (n = 10; LVEF = 25 ± 1%; six males), IMT (n = 11; LVEF = 31 ± 2%; three males), and AET (n = 12; LVEF = 26 ± 2%; seven males). AET, but not IMT, increased the expression of microRNA-1 (P = 0.02; percent changes = 53 ± 17%), decreased the expression of PTEN (P = 0.003; percent changes = -15 ± 0.03%), and tended to increase the p-AKTser473 /AKT ratio (P = 0.06). In addition, AET decreased HDAC4 expression (P = 0.03; percent changes = -40 ± 19%) and upregulated follistatin (P = 0.01; percent changes = 174 ± 58%), MEF2C (P = 0.05; percent changes = 34 ± 15%), and MyoD expression (P = 0.05; percent changes = 47 ± 18%). AET also increased muscle cross-sectional area (P = 0.01). AET and IMT increased LBF, functional capacity, and quality of life. Further analyses showed a significant correlation between percent changes in microRNA-1 and percent changes in follistatin mRNA (P = 0.001, rho = 0.58) and between percent changes in follistatin mRNA and percent changes in peak VO2 (P = 0.004, rho = 0.51).

Conclusions: AET upregulates microRNA-1 levels and decreases the protein expression of PTEN, which reduces the inhibitory action on the PI3K-AKT pathway that regulates the skeletal muscle tropism. The increased levels of microRNA-1 also decreased HDAC4 and increased MEF2c, MyoD, and follistatin expression, improving skeletal muscle regeneration. These changes associated with the increase in muscle cross-sectional area and LBF contribute to the attenuation in skeletal myopathy, and the improvement in functional capacity and quality of life in patients with HFrEF. IMT caused no changes in microRNA-1 and in the downstream-associated pathway. The increased functional capacity provoked by IMT seems to be associated with amelioration in the respiratory function instead of changes in skeletal muscle. ClinicalTrials.gov (Identifier: NCT01747395).

Keywords: Aerobic exercise training; Heart failure; Inspiratory muscle training; MicroRNA-1; Skeletal myopathy.

Conflict of interest statement

The author(s) declare(s) that there is no conflict of interest.

© 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.

Figures

Figure 1
Figure 1
Study design. AET, aerobic exercise training; BMI, body mass index; HFrEF, heart failure with reduced ejection fraction; IMT, inspiratory muscle training; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; VO2, oxygen uptake.
Figure 2
Figure 2
Expression of (A) microRNA‐1 and (B) microRNA‐133a expressed in percent changes (post vs. pre) in control group (control, n = 10), inspiratory muscle training group (IMT, n = 10), and aerobic exercise training group (AET, n = 9). Note that AET provokes a significant increase in expression of microRNA‐1. Values are means ± SE. * vs. pre; P < 0.05.
Figure 3
Figure 3
(A) Representative western blots for statistical results, protein expression of (B) PTEN, (C) PI3K, (D) ratio of phospho‐AKT(ser473)/AKT, and (E) p‐HDAC4ser632. Gene expression of (F) follistatin, (G) MEF2c, and (H) MyoD. The results of protein expression were normalized by Ponceau staining. They are expressed as a percentage of pre expression for each sample in control group (control, n = 10), inspiratory muscle training group (IMT, n = 10), and aerobic exercise training group (AET, n = 9). Note that AET reduces PTEN protein levels, increases PI3K protein levels, and tends to increase p‐AKTser473/AKT ratio (P = 0.06). In addition, AET reduces the protein expression of p‐HDAC4ser632, increases follistatin mRNA levels, increases MEF2c, and increases MyoD mRNA levels. Values are means ± SE. * vs. pre, # vs. control group (percent changes), and †vs. IMT group (percent changes); P < 0.05.
Figure 4
Figure 4
(A) Example of cross‐sectional area of vastus lateralis muscle by one patient from control group (control), inspiratory muscle training group (IMT), and aerobic exercise training group (AET). (B) Cross‐sectional area of vastus lateralis expressed in percent changes (post vs. pre) in control (n = 4), IMT (n = 4), and AET (n = 4). Note that AET increases muscle fibre cross‐sectional area. Values are means ± SE. * vs. pre and # vs control group (percent changes); P < 0.05.
Figure 5
Figure 5
(A) Leg blood flow (LBF), (B) leg vascular conductance (LVC), (C) maximal inspiratory pressure, (D) peak oxygen consumption (peak VO2), (E) peak workload, and (F) Minnesota Living with Heart Failure Questionnaire (MLHFQ) score in control group (control, n = 10), inspiratory muscle training group (IMT, n = 11), and aerobic exercise training group (AET, n = 12). Note that AET and IMT increase LBF and LVC and that the magnitude of changes in LVC is more pronounced in AET group. IMT increases maximal inspiratory pressure. Both AET and IMT increase peak VO2. The peak workload increases in the three groups studied. However, the changes in peak workload in AET group were greater than those found in IMT and control groups. Finally, AET and IMT decrease MLHFQ score. Values are means ± SE. * vs. pre and # vs. control group (delta changes); P < 0.05.
Figure 6
Figure 6
Changes provoked by aerobic exercise training on microRNA‐1 downstream‐associated pathways in patients with chronic heart failure with reduced ejection fraction (HFrEF). Note that despite the increase in microRNA‐1 levels, the PI3K‐AKT pathway is increased, which seems to be associated with a reduction in PTEN levels. In addition, HDAC4 levels decrease, which leads to an increase in follistatin, MEF2C, and MyoD levels. These changes improve protein synthesis, skeletal muscle differentiation, and myocyte fusion. The consequence of such changes is an increase in muscle cross‐sectional area.

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