Mitochondrial Dysfunction in Gulf War Illness Revealed by 31Phosphorus Magnetic Resonance Spectroscopy: A Case-Control Study

Abstract

BackgroundApproximately 1/3 of 1990-1 Gulf War veterans developed chronic multisymptom health problems. Implicated exposures bear mechanisms that adversely affect mitochondria. Symptoms emphasize fatigue, cognition and muscle (brain and muscle are aerobically demanding); with protean additional domains affected, compatible with mitochondrial impairment. Recent evidence supports treatments targeting cell bioenergetics (coenzyme10) to benefit Gulf War illness symptoms. However, no evidence has directly documented mitochondrial or bioenergetic impairment in Gulf War illness.ObjectiveWe sought to objectively assess for mitochondrial dysfunction, examining post-exercise phosphocreatine-recovery time constant (PCr-R) using 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS), in Gulf War veterans with Gulf War illness compared to matched healthy controls. PCr-R has been described as a “robust and practical” index of mitochondrial status.Design and ParticipantsCase-control study from 2012–2013. Fourteen community-dwelling Gulf War veterans and matched controls from the San Diego area comprised 7 men meeting CDC and Kansas criteria for Gulf War illness, and 7 non-deployed healthy controls matched 1∶1 to cases on age, sex, and ethnicity.Outcome MeasureCalf muscle phosphocreatine was evaluated by 31P-MRS at rest, through 5 minutes of foot pedal depression exercise, and in recovery, to assess PCr-R. Paired t-tests compared cases to matched controls.ResultsPCr-R was significantly prolonged in Gulf War illness cases vs their matched controls: control values, mean±SD, 29.0±8.7 seconds; case values 46.1±18.0 seconds; difference 17.1±14.9 seconds; p = 0.023. PCr-R was longer for cases relative to their matched controls for all but one pair; moreover while values clustered under 31 seconds for all but one control, they exceeded 35 seconds (with a spread up to 70 seconds) for all but one case.DiscussionThese data provide the first direct evidence supporting mitochondrial dysfunction in Gulf War illness. Findings merit replication in a larger study and/or corroboration with additional mitochondrial assessment tools.

Translational potential of long-term decreases in mitochondrial lipids in a mouse model of Gulf War Illness

“…There is some evidence that mitochondrial disturbances might be present in veterans with GWI. A small matched case-control study of 31 Phosphorus Magnetic Resonance Spectroscopy showed that veterans with GWI had prolonged post-exercise recovery of muscle phosphocreatine following exercise compared to controls, suggesting defective energy metabolism in the mitochondria (Koslik et al, 2014). As mentioned above, a fMRI study showed impaired lactate utilization as an alternative energy supply in the brains of veterans with GWI (Rayhan et al, 2013a).…”

Coenzyme Q10 Benefits Symptoms in Gulf War Veterans: Results of a Randomized Double-Blind Study

“…Noncompliance is a possibility: participants are veterans with CNS problems, and both cognitive and mood problems have been shown to predict medication noncompliance (Stilley, Sereika, Muldoon, Ryan, & Dunbar-Jacob, 2004). Barriers to assimilation may be present in some; gastrointestinal problems such as diarrhea are not uncommon in GWI, and pancreatic exocrine dysfunction can accompany mitochondrial problems (Hsu et al, 2005), which is reported in GWI (Koslik, Hamilton, & Golomb, 2014). At least one participant acknowledged having disregarded instructions to take one softgel from the smaller bottle or allotment and two daily from the larger, mixing all together.…”

Insomnia Severity, Subjective Sleep Quality, and Risk for Obstructive Sleep Apnea in Veterans With Gulf War Illness

“…43 Recent findings from Beatrice Golcomb’s group 44 provide empirical support for a role of mitochondrial dysfunction and oxidative stress, which promotes and is caused by mitochondrial dysfunction, 45 in GWI. With respect to this finding, it is noteworthy that sleep pathology is a known complication of mitochondrial dysfunction, possibly because cellular energy failure causes both central neurological and peripheral neuromuscular degenerative changes that commonly present as central sleep apnea and poor ventilatory response to hyperapnea.…”