Cai Lun, Swetha Mundanattu, Raji Abraham, Terry Alvin V, Raju Raghavan Pillai
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA; Charlie Norwood Veterans Affairs Medical Center, Augusta, GA, USA.
Redox Biol. 2025 Jun 4;85:103714. doi: 10.1016/j.redox.2025.103714.
Gulf War Illness (GWI) is a cluster of medically unexplained chronic symptoms, including neurological and gastrointestinal impairments, and muscle fatigue, suffered by veterans of the Persian Gulf War. A GWI model in C57BL/6 mice exposed to the nerve gas prophylactic pyridostigmine-bromide (PB) and the insecticide permethrin (PER) was used to test the effect of mitochondria-potentiating agents, metformin and MitoQ on chronic fatigue, observed in GWI. The exposure of mice to PB/PER resulted in enhanced oxidative stress, impaired mitochondrial function, and reduced autophagy. Treatment with the anti-diabetic drug metformin and the mitochondria-targeted antioxidant available as a dietary supplement, MitoQ, activated the AMPK signaling, reduced oxidative stress, and attenuated inflammation in gastrocnemius muscle tissue compared to untreated mice. The combination of metformin and MitoQ was found to be more effective than the individual treatments in activating AMPK. The combination treatment rescued autophagy and improved mitochondrial respiration. Chronic fatigue assessments by the hanging wire and rotarod tests, and voluntary wheel running activities showed improved physical activity/strength in mice treated with metformin and MitoQ. The results suggest the potential therapeutic benefit of a combination formulation of metformin and MitoQ in addressing the molecular and energetic impairments of skeletal muscle in GWI.
海湾战争综合征（GWI）是一组无法用医学解释的慢性症状，包括神经和胃肠道损伤以及肌肉疲劳，波斯湾战争退伍军人会出现这些症状。在暴露于神经毒气预防剂溴化吡啶斯的明（PB）和杀虫剂氯菊酯（PER）的C57BL/6小鼠中建立了GWI模型，以测试线粒体增强剂二甲双胍和MitoQ对GWI中观察到的慢性疲劳的影响。小鼠暴露于PB/PER会导致氧化应激增强、线粒体功能受损和自噬减少。与未治疗的小鼠相比，用抗糖尿病药物二甲双胍和作为膳食补充剂的线粒体靶向抗氧化剂MitoQ进行治疗，可激活AMPK信号传导、降低氧化应激并减轻腓肠肌组织中的炎症。发现二甲双胍和MitoQ的组合在激活AMPK方面比单独治疗更有效。联合治疗挽救了自噬并改善了线粒体呼吸。通过悬线和转棒试验以及自愿轮跑活动进行的慢性疲劳评估显示，用二甲双胍和MitoQ治疗的小鼠的身体活动/力量有所改善。结果表明，二甲双胍和MitoQ的组合制剂在解决GWI中骨骼肌的分子和能量损伤方面具有潜在的治疗益处。
