Diagnostic Utility of mtDNA Content and Exercise Challenge in Veterans with GWI

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DESCRIPTION (provided by applicant): One in four of the ~700,000 Veterans who served in the 1990 - 1991 Gulf War suffer from chronic multisystem illnesses, referred to as Gulf War Illness (GWI). GWI symptoms vary from fatigue and pain to cognitive dysfunction and sleep disturbances, but have been difficult to quantify and treat sometimes leading to their dismissal. That difficulty persists in characterizing what is known as GWI does not negate its existence. To this end, the scientific and medical communities are challenged to develop new diagnostic indicators that may lead to an enhanced understanding of the underlying pathophysiology of GWI and an ability to differentiate those with and without GWI. GWI is often characterized by its variability; however, there is some uniformity that warrants attention. For example, the diverse symptomatology involves multiple high-energy organ systems (e.g. muscular, central/autonomic nervous, respiratory, and gastrointestinal). Proper functioning of these systems requires efficiency on part of the mitochondria. According to the NIH, individuals with mitochondrial dysfunction or disease also present with a heterogeneous mix of symptoms that include exercise intolerance, fatigue, headache, and general weakness - symptoms shared with GWI. Additionally, mitochondrial DNA (mtDNA) damage is positively associated with exposure to particulate matter, benzene, and polycyclic aromatic hydrocarbons in humans. Therefore, analysis of mtDNA [and respiratory chain enzyme activity] may be an excellent candidate biomarker for endogenous and exogenous exposures of GWI. Damage to mtDNA would also likely affect exercise performance given the high-energy demands, resulting in profound fatigue and abnormal recovery. However, the literature in GWI has been mixed. Similar contradictory results have also been observed in individuals with chronic fatigue syndrome (CFS) - yet recent data suggests that these mixed results are accounted for by the limitation of a single exercise test which fails to consider the post-exertional malaise period characteristic to those with GWI and CFS. However, performing a second exercise test 24 hours after the first (i.e. repeated-bout) results in sizeable and significant differences between those with and without CFS. We suspect this repeated-bout exercise test paradigm will be of similar utility in this pilot study and be capable of differentiting those with and without GWI. [We propose to study independent and complementary markers of mitochondrial damage and dysfunction (i.e. mtDNA content, respiratory chain enzyme activity) and the response to a repeated-bout exercise test (i.e. breath-by-breath metabolic data, lactate, etc.) as a means of diagnostic testing for GWI.] Data derived from this pilot study may not only be important as potential objective indicators, but may also significantly improve our understanding of the GWI pathophysiology. Additionally, the potential translational merits could be rapid as efficacious treatment is currently available for mitochondrial dysfunction.