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

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

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.

Highlights

Activation of AMPK has been associated with pro-atrophic signaling in muscle
While AMPK has been associated with the progression of cachexia, its anti-inflammatory properties suggest that AMPK activation could be anti-cachectic, since inflammation is the primary driver of cachectic muscle wasting (Tisdale, 2009)
To understand whether AMPK activation could prevent inflammation-driven atrophy, we tested the effects of drug-induced AMPK activation in models of inflammatory muscle wasting

Summary

Introduction

AMPK has anti-inflammatory effects, suggesting that in cachexia, a syndrome of inflammatory-driven muscle wasting, AMPK activation could be beneficial. We show that the AMPK agonist AICAR suppresses IFNc/TNFa-induced atrophy, while the mitochondrial inhibitor metformin does not. 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. Our findings suggest a dual function for AMPK during inflammationdriven 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

Methods

Results

Conclusion