Impact of transcutaneous neuromuscular electrical stimulation or resistance exercise on skeletal muscle mRNA expression in COPD

Abstract

Background: Voluntary resistance exercise (RE) training increases muscle mass and strength in patients with chronic obstructive pulmonary disease (COPD). Nonvolitional transcutaneous neuromuscular electrical stimulation (NMES) may be an alternative strategy for reducing ambulatory muscle weakness in patients unable to perform RE training, but little comparative data are available. This study, therefore, investigated changes in muscle mRNA abundance of a number of gene targets in response to a single bout of NMES compared with RE.

Methods: Twenty-six patients with stable COPD (15 male; FEV₁, 43±18% predicted; age, 64±8 years; fat free mass index, 16.6±1.8 kg/m²) undertook 30 minutes of quadriceps NMES (50 Hz, current at the limit of tolerance) or 5×30 maximal voluntary isokinetic knee extensions. Vastus lateralis muscle biopsies were obtained at rest immediately before and 24 hours after intervention. Expression of 384 targeted mRNA transcripts was assessed by real time TaqMan PCR. Significant change in expression from baseline was determined using the ΔΔC_T method with a false discovery rate (FDR) of <5%.

Results: NMES and RE altered mRNA abundance of 18 and 68 genes, respectively (FDR <5%), of which 14 genes were common to both interventions and of the same magnitude of fold change. Biological functions of upregulated genes included inflammation, hypertrophy, muscle protein turnover, and muscle growth, whilst downregulated genes included mitochondrial and cell signaling functions.

Conclusions: Compared with NMES, RE had a broader impact on mRNA abundance and, therefore, appears to be the superior intervention for maximizing transcriptional responses in the quadriceps of patients with COPD. However, if voluntary RE is not feasible in a clinical setting, NMES by modifying expression of genes known to impact upon muscle mass and strength may have a positive influence on muscle function.

Keywords:

• COPD
• NMES
• skeletal muscle
• gene expression
• resistance exercise

Acknowledgment

We thank the patients who volunteered for this study.

Ethics approval and consent to participate

Ethical approval was granted by the UK National Health Service (NHS) Research Ethics Committee (REC) (NMES Study: West Midlands REC, reference 10/H1208/73; RE Study: Leicestershire, Northamptonshire, and Rutland REC, reference 05/Q2502/131) and participants provided written informed consent.

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding

This work was supported by the Medical Research Council [grant number MR/P021220/1]. This research was also supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care Leicestershire Nothamptonshire and Rutland (CLAHRC LNR), UK, and by CLAHRC East Midlands, and by the NIHR Leicester Biomedical Research Centre - Respiratory, at the University Hospitals of Leicester NHS Trust, UK. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. This work was partly funded by Remedi: Enabling Research in Rehabilitation (a UK registered charity; 1063359). Study funders did not participate in study design, data interpretation, or manuscript presentation.

LL was supported by the NIHR Leicester Biomedical Research Centre - Respiratory. DC was supported by the Medical Research Council/Arthritis Research UK (MRC/ARUK) Centre for Musculoskeletal Ageing Research.

Author contributions

LEL assessed patients, performed laboratory analysis, processed the dataset, performed statistical analysis, and drafted the manuscript. DC performed laboratory analysis and contributed to data interpretation. NJG, LC, and MKM recruited volunteers, and performed patient assessments and muscle biopsies. MCS and PLG made substantial contributions to the design of the study, oversaw analysis, and made substantial contributions to the interpretation of the data. All authors contributed towards data analysis, drafting and critically revising the paper, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.

Disclosure

NJG reports personal fees from AstraZeneca, GlaxoSmithKline (GSK), and Boehringer Ingelheim outside the submitted work. MCS reports personal fees and non-financial support from Boehringer Ingelheim, GSK and Nutricia outside the submitted work, and grants from the Medical Research Council and NIHR East Midlands CLAHRC during the conduct of the study. PLG reports grants from the MRC/ARUK Centre for Musculoskeletal Ageing Research, and a grant from Remedi, during the conduct of the study. LEL was funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care, Leicestershire, Northamptonshire, and Rutland (CLAHRC LNR); CLAHRC East Midlands; and the NIHR Leicester Biomedical Research Centre – Respiratory, who also provided facilities at the University Hospitals of Leicester NHS Trust during the conduct of the study. DC was funded by the MRC/ARUK Centre for Musculoskeletal Ageing Research during the conduct of this study. The authors report no other conflicts of interest in this work.