Skeletal muscle vasomotor function, ergonomics, histopathology, and gene expression in Veterans with Gulf War Illness

Abstract Background Gulf War Illness (GWI) is a constellation of debilitating symptoms including fatigue and muscle weakness reported in one-third of Veterans from coalition countries deployed in the Gulf War (1990-1991). We hypothesized that muscle vasomotor function, physiology, structure, and gene expression were different between 49 cases with GWI and 22 controls Veterans defined by the symptom-based Kansas GWI questionnaire. Methods We assessed profunda artery microvascular vasomotion with intra-arterial infusions of acetylcholine 10 −4 M (endothelium-dependent) and adenosine (endothelium-independent), and aerobic function by a symptom-limited cardiopulmonary exercise test. Biopsies of the vastus lateralis were frozen for later histology, western blot analysis, and unbiased gene expression using bulk RNA sequencing (RNAseq). Results Veteran GWI cases and controls have similar microvascular endothelium-dependent function (difference = −6.6%, 95%CI = −31.5%, 18.4%), endothelium independent function (difference = −10%, 95%CI = −95%, 75%) vasomotor function. The study has adequate power to identify known factors related to impaired microvascular endothelium-dependent function, such as smoking (difference = −42.5%, 95%CI = −79.0%, − 6.0%). Cases and controls have similar aerobic capacity (difference peak V̇O 2 = −1.5, 95%CI = −4.8, 1.9 mL/kg/min), V̇O 2 at anabolic threshold (difference = −1.0, 95%CI = −4.1, 2.1 mL/kg/min). Cases and controls have similar muscle histology, mitochondrial volume and density, and content of glycolytic, anerobic, tricarboxylic acid cycle and mitochondrial oxidative phosphorylation enzymes. RNAseq reveals no metabolic pathway gene dysregulation associated with GWI. Conclusions Symptoms of GWI triggered by the physical and psychological trauma of war are unrelated to multiple peripheral vascular and muscle parameters. GWI patients should obtain a similar training effect from physical activity as those without GWI.