The AMPK agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wasting

作者：Derek Hall, Takla Griss, F. Jennifer, Brenda Janice Sánchez, Jason Sadek, Anne Marie K Tremblay, Souad Mubaid, Amr Omer, Rebecca J. Ford, Nathalie Bédard, Arnim Pause, Simon S. Wing, Sergio Di Marco, Gregory R. Steinberg, Russell G. Jones, Imed‐Eddine Gallouzi · 发表于：EMBO Molecular Medicine · 年份：2018 · DOI：10.15252/emmm.201708307 · 被引用次数：88 · 研究领域：Metabolism, Diabetes, and Cancer、Muscle Physiology and Disorders、Parkinson's Disease Mechanisms and Treatments

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.