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EMBO Mol Med. 2018 Jul;10(7). pii: e8307. doi: 10.15252/emmm.201708307.

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

Author information

1
Department of Biochemistry, McGill University, Montreal, QC, Canada.
2
Rosalind and Morris Goodman Cancer Centre, Montreal, QC, Canada.
3
Department of Physiology, McGill University, Montreal, QC, Canada.
4
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON, Canada.
5
Department of Medicine, McGill University and the Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
6
Department of Biochemistry, McGill University, Montreal, QC, Canada imed.gallouzi@mcgill.ca igallouzi@qf.org.qa.
7
Life Sciences Division, College of Sciences and Engineering, Hamad Bin Khalifa University (HBKU), Doha, Qatar.

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.

KEYWORDS:

AMPK ; iNOS ; cachexia; inflammation; metabolism

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