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

EMBO Molecular Medicine
Derek T HallImed-Eddine Gallouzi

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 subse...Continue Reading

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Citations

Apr 5, 2019·Current Opinion in Clinical Nutrition and Metabolic Care·Janice Miller, Richard J E Skipworth
Sep 15, 2019·Nature Communications·Brenda Janice SánchezImed-Eddine Gallouzi
Aug 14, 2019·Proceedings of the National Academy of Sciences of the United States of America·Souad MubaidImed-Eddine Gallouzi
Jun 18, 2020·Frontiers in Immunology·Margaret A McBrideNaeem K Patil
Jul 28, 2020·Molecular and Cellular Biochemistry·Guadalupe Martínez-ChacónAlberto Ballestín
Jan 14, 2021·Nature Communications·Roberta SartoriMarco Sandri
Dec 31, 2020·International Journal of Molecular Sciences·Rizwan QaisarHolly Van Remmen
Jan 6, 2021·Endocrinology and Metabolism·Tam DaoDongryeol Ryu
Mar 31, 2021·Journal of Cachexia, Sarcopenia and Muscle·Agnès Martin, Damien Freyssenet
Nov 3, 2021·Journal of Cachexia, Sarcopenia and Muscle·Min Ju KangHyeon Soo Kim
Dec 5, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Fatemeh FattahiUlus Atasoy

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Methods Mentioned

BETA
light microscopy
Assay
electrophoresis
Transfection

Software Mentioned

EG
GraphPad Prism
GraphPad
ImageJ
AICAR
AxioVision

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