Exercise-induced changes in gene expression do not mediate post exertional malaise in Gulf War illness

Abstract

Background: Post-exertional malaise (PEM) is considered a characteristic feature of chronic multi-symptom illnesses (CMI) like Gulf War illness (GWI); however, its pathophysiology remains understudied. Previous investigations in other CMI populations (i.e., Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) have reported associations between PEM and expression of genes coding for adrenergic, metabolic, and immune function.

Objectives: To investigate whether PEM is meditated by gene expression in Veterans with GWI.

Methods: Veterans with GWI (n = 37) and healthy control Gulf War Veterans (n = 25) provided blood samples before and after 30-min of cycling at 70% of age-predicted heart rate reserve. Relative quantification of gene expression, symptom measurements, and select cardiopulmonary parameters were compared between groups at pre-, 30 minpost-, and 24 hpost-exercise using a doubly multivariate repeated measures analysis of variance (RM-MANOVA). Mediation analyses were used to test indirect effects of changes in gene expression on symptom responses (i.e., PEM) to the standardized exercise challenge.

Results: Veterans with GWI experienced large symptom exacerbations following exercise compared to controls (Cohen's d: 1.65; p < 0.05). Expression of $\beta$ -actin (ACTB), catechol-O-methyltransferase (COMT), and toll-like receptor 4 (TLR4) decreased in Veterans with GWI at 30 min (p < 0.05) and 24 h post-exercise (p < 0.05). Changes in gene expression did not mediate post-exercise symptom exacerbation in GWI (Indirect Effect Slope Coefficient: 0.06 - 0.02; 95% CI: 0.19, 0.12).

Conclusion: An acute bout of moderate intensity cycling reduced the expression of select structural, adrenergic, and immune genes in Veterans with GWI, but the pathophysiological relevance to PEM is unclear.

Keywords: Exercise test; Gulf war; MeSH terms: Gene expression; Mediation analysis; Symptom flare up; Veterans health.

Fig. 1

Peak PEM Scores (CDC VAS) in Veterans with GWI and Veteran CON at 24hr Post-Exercise Note. Veterans with GWI had significant symptom exacerbation (Mean = 41.38, SD = 27.87) compared to CON Veterans (Mean = 4.80, SD = 7.80) at 24 h post-exercise. For each participant, PEM score was defined as the greatest increase in severity across 19 different symptoms at 24 h post-exercise, as measured by 0–100 visual analog scales on the CDC symptom inventory Means are denoted by solid black lines, while the thin dashed lines represent the first and third quartiles.

Fig. 2

Visual representation of genes showing significant main effect for group Note. Pre-exercise gene expression was relativized to a value of 1.0 (gray bar). A significant main effect of group was observed for ACTB (Main Effect: partial $\eta$² = 0.09, 95% CI = 0.01, 1.00; 30 min post: p = 0.02; 24 h post: p = 0.04), COMT (Main Effect: partial $\eta$² = 0.10, 95% CI = 0.01, 1.00; 30 min post: p = 0.02; 24 h post: p = 0.04), TLR4 (Main Effect: partial $\eta$² = 0.10, 95% CI = 0.01, 1.00; 30 min post: p = 0.01; 24 h post: p = 0.03) at both 30 min and 24 h post-exercise as detected by RM-ANOVA.