Chronic Fatigue in a Mouse Model of Gulf War Illness

Abstract

The Gulf War, a war fought in the deserts of Saudi Arabia, left a quarter of US troops debilitated with a set of symptoms known as Gulf War Illness (GWI). These include neurological impairments, gastrointestinal disturbances and chronic fatigue suggesting that gut‐brain interactions may be provoking metabolic dysfunction leading to chronic fatigue. This study was focused on establishing a mouse model of GWI to better understand the etiology and pathophysiology of chronic fatigue in GWI. This study tested the hypothesis that GWI mice exposed to GW agents (acetylcholinesterase inhibitor, pyridostigmine bromide (PB), the insecticide permethrin, and the insect repellant, N,N‐Diethyl‐meta‐toluomide (DEET), and restraint stress, would produce exercise intolerance and resting and post‐exercise metabolic dysfunction. To simulate the route/duration in troop exposure, adult male C57B16/N mice were given PB (13 mg/kg, oral gavage), permethrin (0.3 mg/kg, 70% ethanol, top) and DEET (40 mg/kg; 70% ethanol, top) daily for 5d/wk X 4 wk. Mice were also exposed to 5min restraint stress. Sham controls received saline gavage, topical alcohol and restraint stress. Testing was conducted 1wk after exposure (PT) and at 90d PT. Fasted mice were subjected to an insulin tolerance test (0.5U/kg Humulin N i.p.) and blood glucose measured subsequently. One week later, mice were subjected to a 5‐day exercise endurance (EE) test to test for fatigue. Specific criteria were established to confirm the determination of exhaustion. During optimization of the EE test (3d training, 2d testing), we found that motivating mice to run for over 20min was feasible without electric shock. On exercise endurance, GW exposure produced a decreased latency to fatigue relative to sham (p<.05). GW mice showed exercise exhaustion relative to the sham controls immediately following post‐treatment (PT) (15.4 +/− 2.6 min), and at 90PT (8.7 +/− 1.3 min). Corresponding values for sham were (23.5 +/− 2.5 min), and (26.8 +/− 5.1 min), respectively. These mean values show a significantly lesser latency to exhaustion that persisted in for GW relative to sham. Metabolic measures taken immediately after EE showed incremental elevations in post‐exercise lactate levels in GW mice relative to their pre‐treatment control (p<0.001 n=6–7/per group). In contrast, shams showed similar post‐exercise lactate elevations at pre‐treatment, PT and PT90. Mean (+/− sem) values were 6.1 +/− 0.38 mmol/dL pre‐treatment, 6.1 +/− 0.4 mmol/dL at PT and 6.8 +/− 1.8 mmol/dL at PT90. Insulin injection reduced average glycemia to a greater peak in sham than in GW, i.e., 64.1% vs 78% baseline (p<.05, n=3–6/group) but the latter normalized at PT90. In combination, our results show that GW agents reduce time to exercise exhaustion, and produce abnormal post‐exercise metabolism and insulin insensitivity that may explain, in part, chronic fatigue in GWI.Support or Funding InformationAmerican Physiological Society (A.B.) and UC Minigrant (A.B. and J.T.)