Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS.

Audrey E Brown,Julia L Newton,Beth Dibnah,Emily Fisher,Mark Walker

doi:10.1042/bsr20180242

Audrey E Brown, Julia L Newton + Show 3 more

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https://doi.org/10.1042/bsr20180242

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Journal: Bioscience reports	Publication Date: May 8, 2018
Citations: 20	License type: CC BY 4.0

Affiliation: Newcastle University

Abstract

Skeletal muscle fatigue and post-exertional malaise are key symptoms of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (ME/CFS). We have previously shown that AMP-activated protein kinase (AMPK) activation and glucose uptake are impaired in primary human skeletal muscle cell cultures derived from patients with ME/CFS in response to electrical pulse stimulation (EPS), a method which induces contraction of muscle cells in vitro. The aim of the present study was to assess if AMPK could be activated pharmacologically in ME/CFS. Primary skeletal muscle cell cultures from patients with ME/CFS and healthy controls were treated with either metformin or compound 991. AMPK activation was assessed by Western blot and glucose uptake measured. Both metformin and 991 treatment significantly increased AMPK activation and glucose uptake in muscle cell cultures from both controls and ME/CFS. Cellular ATP content was unaffected by treatment although ATP content was significantly decreased in ME/CFS compared with controls. Pharmacological activation of AMPK can improve glucose uptake in muscle cell cultures from patients with ME/CFS. This suggests that the failure of EPS to activate AMPK in these muscle cultures is due to a defect proximal to AMPK. Further work is required to delineate the defect and determine whether pharmacological activation of AMPK improves muscle function in patients with ME/CFS.

Highlights

Chronic fatigue syndrome (CFS), known as myalgic encephalomyelitis (ME), is a long-term illness affecting approximately 250000 people in the U.K., and has a wide range of symptoms
We have previously shown that AMP-activated protein kinase (AMPK) activation is impaired in primary human skeletal muscle cell cultures derived from patients with ME/CFS in response to electrical pulse stimulation (EPS), a method which induces contraction of muscle cells in vitro [5]
Acetyl-CoA Carboxylase (ACC) phosphorylation increased in a dose-dependent manner in response to compound 991

Summary

Introduction

Chronic fatigue syndrome (CFS), known as myalgic encephalomyelitis (ME), is a long-term illness affecting approximately 250000 people in the U.K., and has a wide range of symptoms. In response to an energy deficit, such as during muscle contraction, AMPK is activated resulting in the switching off of ATP-consuming processes, and the switching on of ATP-generating processes In skeletal muscle, this includes an increase in the uptake of glucose into the muscle cell [4]. We have previously shown that AMPK activation is impaired in primary human skeletal muscle cell cultures derived from patients with ME/CFS in response to electrical pulse stimulation (EPS), a method which induces contraction of muscle cells in vitro [5] This abnormality in AMPK activation resulted in a failure to increase glucose uptake into the cell in response to EPS. We used both an indirect activator of AMPK (metformin) and a direct activator (Compound 991) to assess AMPK activation, glucose uptake and ATP content of muscle cells

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