Induction of Muscle Atrophy and Loss of Muscle Function by Gulf‐War Illness Associated Chemicals: Underlying Mechanisms

Abstract

Gulf War illness (GWI) afflicts ~30% of US retired military personnel whom served at Persian Gulf War (GW) of 1990–91 (~450,000 men and women). GWI comprises a gathering of symptoms mainly affecting nervous and skeletal muscle (SkM) systems. The syndrome includes cognitive deficits, depression, muscle pain, weakness, intolerance to exercise and fatigue. Affected Veterans continue to experience altered behavior and other symptoms after 25 years of exposure to suspect chemicals. Co‐exposure to specific chemical agents and stress are suspected to be the cause of such disorder. GW military personnel consumed daily pyridostigmine (PB) tablets as a prophylactic treatment to protect from nerve gas attacks during the war. In addition, to reduce the risk of infection by communicable (insect borne) diseases troop/staff members were also exposed to insecticides and insect repellents, most commonly permetrim (PM) and N;N‐diethyl‐m‐toluamide (DEET). VA investigators have developed and validated rodent models of GWI like exposure by providing them with equivalent doses of chemicals for limited periods of time (up to 4 weeks). Whereas a significant amount of knowledge is available about the effects of such treatments on neurological structure and function, very little is known about the effects on skeletal muscle (SkM). We implemented a rat model of GWI to examine changes in SkM structure and function including tissue wasting pathways. Three month old male Wistar rats (n=9) were provided orally with PB 1.3 mg/kg/day, PM 0.13 mg/kg/day (back skin) and DEET 40 mg/kg/day (back skin), and physically restricted them for five minutes for a total of 3 weeks. An additional 3 week period was allowed to develop the intoxication (intox) profile. A control group (n=9), were administered vehicles and did not receive physical restraint. After the intoxication period, animals were subjected to treadmill and limb strength testing. Afterwards, animals were euthanized and SkM (gastrocnemius) samples collected and processed for histological, biochemical and Western blot analysis. Prior to euthanasia, GWI animals did not evidence significant changes in body weight vs. controls. In contrast, grastrocnemius weight and size from intoxicated animals was ~35% significantly lower vs. controls, which was consistent with recorded significant decreases in SkM myofiber area, limb strength (see figure) and treadmill distance (~30–50%). SkM immunostaining of GWI samples evidence the MyHC (α/β) ratio increase vs. controls. Western blot analysis of follistatin, ACTA‐1, CKm, MYH protein levels were significantly decreased (up to 80%) in the GWI group. Wasting pathway related proteins levels such as myostatin, MURF1, FAbx, atrogin and proteasome 20s were significantly increased (up to 80%) in GWI rats. Altogether, results indicate that exposure of rodents to equivalent human doses of associated GWI chemicals can activate muscle atrophy pathways leading to a severe loss of organ function. Further studies are needed to identify the specific causal agent(s) and risks of human exposure.Support or Funding InformationNIH DK98717 to FVThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.