The AMPK agonist AICAR, but not metformin, prevents inflammation-associated cachectic muscle wasting

Activation of AMPK has been associated with pro-atrophic signaling in muscle. However, AMPK also has anti-inflammatory effects, suggesting that in cachexia, a syndrome of inflammatory-driven muscle wasting, AMPK activation could be beneficial. Here we show that the AMPK agonist AICAR suppresses IFNγ/TNFα-induced atrophy, while the mitochondrial inhibitor, metformin, does not. IFNγ/TNFα impair mitochondrial oxidative respiration in myotubes and promote a metabolic shift to aerobic glycolysis, similarly to metformin. In contrast, AICAR partially restored metabolic function. The effects of AICAR were prevented by the AMPK inhibitor Compound C and were reproduced with A-769662, a specific AMPK activator. AICAR and A-769662 co-treatment was found to be synergistic, suggesting that the anti-cachectic effects of these drugs are mediated through AMPK activation. AICAR spared muscle mass in mouse models of cancer and LPS induced atrophy. Together, our findings suggest a dual function for AMPK during inflammation-driven atrophy, wherein it can play a protective role when activated exogenously early in disease progression, but may contribute to anabolic suppression and atrophy when activated later through mitochondrial dysfunction and subsequent metabolic stress.

腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK）的激活与肌肉组织的促萎缩信号通路密切相关。然而，AMPK同时兼具抗炎活性，这提示在以炎症介导肌肉消耗为特征的恶病质综合征中，AMPK激活或可发挥有益作用。本研究证实，AMPK激动剂AICAR可抑制干扰素γ（Interferon γ, IFNγ）与肿瘤坏死因子α（Tumor Necrosis Factor α, TNFα）诱导的肌肉萎缩，而线粒体抑制剂二甲双胍则无法产生此类抑制效应。IFNγ与TNFα可损伤肌管细胞的线粒体氧化呼吸功能，并促使代谢转向有氧糖酵解，该效应与二甲双胍的作用模式一致。与之相反，AICAR可部分恢复受损的代谢功能。AICAR的上述作用可被AMPK抑制剂Compound C阻断，且通过特异性AMPK激活剂A-769662可重现该效应。研究发现，AICAR与A-769662联合给药具有协同效应，表明这两类药物的抗恶病质作用均通过AMPK激活介导。AICAR可在癌症恶病质及脂多糖（Lipopolysaccharide, LPS）诱导的肌肉萎缩小鼠模型中保留肌肉质量。综上，本研究结果提示AMPK在炎症介导的肌肉萎缩过程中发挥双重功能：在疾病进展早期外源性激活AMPK，可发挥保护性作用；但若在疾病后期因线粒体功能障碍及继发代谢应激而激活AMPK，则可能加剧合成代谢抑制与肌肉萎缩。