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

EMBO Molecular Medicine

Amr Omer¹  Jason Sadek¹  Souad Mubaid¹  Anne Marie K Tremblay¹  Sergio Di Marco¹  Derek T Hall¹  Imed‐Eddine Gallouzi¹  Arnim Pause¹  Brenda Janice Sanchez¹  Jennifer F Ma¹  Simon S Wing²  Nathalie Bedard²  Gregory R Steinberg³  Rebecca J Ford³  Russell G Jones⁴  Takla Griss⁴ 

[1] Department of Biochemistry McGill University Montreal QC Canada;Department of Medicine McGill University and the Research Institute of the McGill University Health Centre Montreal QC Canada;Division of Endocrinology and Metabolism Department of Medicine McMaster University Hamilton ON Canada;Rosalind and Morris Goodman Cancer Centre Montreal QC Canada;

关键词: AMPK;    cachexia;    inflammation;    iNOS;    metabolism;   

DOI  :  10.15252/emmm.201708307

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown