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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / therapeutic use
  • Animals
  • Cachexia / etiology
  • Cachexia / prevention & control*
  • Cell Line
  • Enzyme Activation
  • Inflammation / complications
  • Interferon-gamma / antagonists & inhibitors
  • Male
  • Metformin / therapeutic use*
  • Mice, Inbred BALB C
  • Mitochondria / drug effects
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / enzymology
  • Neoplasms, Experimental / pathology
  • Nitric Oxide Synthase Type II / metabolism
  • Protein Kinases / drug effects
  • Protein Kinases / metabolism*
  • Ribonucleotides / therapeutic use*
  • Shock, Septic / chemically induced
  • Shock, Septic / complications
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors

Substances

  • Ribonucleotides
  • Tumor Necrosis Factor-alpha
  • Aminoimidazole Carboxamide
  • Interferon-gamma
  • Metformin
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • AICA ribonucleotide