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Introduction The components of minute ventilation, respiratory frequency and tidal volume, appear differentially regulated and thereby afford unique insight into the ventilatory response to exercise. However, respiratory frequency and tidal volume are infrequently reported, and have not previously been considered among military veterans with Gulf War Illness. Our purpose was to evaluate respiratory frequency and tidal volume in response to a maximal cardiopulmonary exercise test in individuals with and without Gulf War Illness. Materials and methods 20 cases with Gulf War Illness and 14 controls participated in this study and performed maximal cardiopulmonary exercise test on a cycle ergometer. Ventilatory variables (minute ventilation, respiratory frequency and tidal volume) were obtained and normalized to peak exercise capacity. Using mixed-design analysis of variance models, with group and time as factors, we analyzed exercise ventilatory patterns for the entire sample and for 11 subjects from each group matched for race, age, sex, and height. Results Despite similar minute ventilation (p = 0.57, η2p = 0.01), tidal volume was greater (p = 0.02, η2p = 0.16) and respiratory frequency was lower (p = 0.004, η2p = 0.24) in Veterans with Gulf War Illness than controls. The findings for respiratory frequency remained significant in the matched subgroup (p = 0.004, η2p = 0.35). Conclusion In our sample, veterans with Gulf War Illness adopt a unique exercise ventilatory pattern characterized by reduced respiratory frequency, despite similar ventilation relative to controls. Although the mechanism(s) by which this pattern is achieved remains unresolved, our findings suggest that the components of ventilation should be considered when evaluating clinical conditions with unexplained exertional symptoms.

Gulf War Illness (GWI) is a chronic multi-symptom illness not currently diagnosed by standard medical or laboratory test that affects 30% of veterans who served during the 1990-1991 Gulf War. The clinical presentation of GWI is comparable to that of patients with certain mitochondrial disorders-i.e., clinically heterogeneous multisystem symptoms. Therefore, we hypothesized that mitochondrial dysfunction may contribute to both the symptoms of GWI as well as its persistence over time. We recruited 21 cases of GWI (CDC and Kansas criteria) and 7 controls to participate in this study. Peripheral blood samples were obtained in all participants and a quantitative polymerase chain reaction (QPCR) based assay was performed to quantify mitochondrial and nuclear DNA lesion frequency and mitochondrial DNA (mtDNA) copy number (mtDNAcn) from peripheral blood mononuclear cells. Samples were also used to analyze nuclear DNA lesion frequency and enzyme activity for mitochondrial complexes I and IV. Both mtDNA lesion frequency (p = 0.015, d = 1.13) and mtDNAcn (p = 0.001; d = 1.69) were elevated in veterans with GWI relative to controls. Nuclear DNA lesion frequency was also elevated in veterans with GWI (p = 0.344; d = 1.41), but did not reach statistical significance. Complex I and IV activity (p0.05) were similar between groups and greater mtDNA lesion frequency was associated with reduced complex I (r2 = -0.35, p = 0.007) and IV (r2 = -0.28, p0.01) enzyme activity. In conclusion, veterans with GWI exhibit greater mtDNA damage which is consistent with mitochondrial dysfunction.

Gulf War Illness (GWI) is a chronic multi-symptom illness not currently diagnosed by standard medical or laboratory test that affects 30% of veterans who served during the 1990-1991 Gulf War. The clinical presentation of GWI is comparable to that of patients with certain mitochondrial disorders-i.e., clinically heterogeneous multisystem symptoms. Therefore, we hypothesized that mitochondrial dysfunction may contribute to both the symptoms of GWI as well as its persistence over time. We recruited 21 cases of GWI (CDC and Kansas criteria) and 7 controls to participate in this study. Peripheral blood samples were obtained in all participants and a quantitative polymerase chain reaction (QPCR) based assay was performed to quantify mitochondrial and nuclear DNA lesion frequency and mitochondrial DNA (mtDNA) copy number (mtDNAcn) from peripheral blood mononuclear cells. Samples were also used to analyze nuclear DNA lesion frequency and enzyme activity for mitochondrial complexes I and IV. Both mtDNA lesion frequency (p = 0.015, d = 1.13) and mtDNAcn (p = 0.001; d = 1.69) were elevated in veterans with GWI relative to controls. Nuclear DNA lesion frequency was also elevated in veterans with GWI (p = 0.344; d = 1.41), but did not reach statistical significance. Complex I and IV activity (p > 0.05) were similar between groups and greater mtDNA lesion frequency was associated with reduced complex I (r2 = -0.35, p = 0.007) and IV (r2 = -0.28, p < 0.01) enzyme activity. In conclusion, veterans with GWI exhibit greater mtDNA damage which is consistent with mitochondrial dysfunction.