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

Derek T. Hall, Takla Griss, Jennifer F. Ma, Brenda Janice Sanchez, Jason Sadek, Anne Marie K. Tremblay, Souad Mubaid, Amr Omer, Rebecca J. Ford, Nathalie Bedard, Arnim Pause, Simon S. Wing, Sergio Di Marco, Gregory R. Steinberg, Russell G. Jones, Imed Gallouzi

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13 Citations (Scopus)

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.

Original languageEnglish
JournalEMBO Molecular Medicine
DOIs
Publication statusAccepted/In press - 1 Jan 2018

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Keywords

  • AMPK
  • Cachexia
  • Inflammation
  • iNOS
  • Metabolism

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Hall, D. T., Griss, T., Ma, J. F., Sanchez, B. J., Sadek, J., Tremblay, A. M. K., Mubaid, S., Omer, A., Ford, R. J., Bedard, N., Pause, A., Wing, S. S., Di Marco, S., Steinberg, G. R., Jones, R. G., & Gallouzi, I. (Accepted/In press). The AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation-associated cachectic muscle wasting. EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201708307