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Diabetologia
Published in: Diabetologia 9/2010

01-09-2010 | Article

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

Authors: S. A. Crawford, S. R. Costford, C. Aguer, S. C. Thomas, R. A. deKemp, J. N. DaSilva, D. Lafontaine, M. Kendall, R. Dent, R. S. B. Beanlands, R. McPherson, M.-E. Harper

Published in: Diabetologia | Issue 9/2010

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Abstract

Aims/hypothesis

AMP-activated protein kinase (AMPK) has a broad role in the regulation of glucose and lipid metabolism making it a promising target in the treatment of type 2 diabetes mellitus. We therefore sought to characterise for the first time the effects of chronic AMPK activation on skeletal muscle carbohydrate metabolism in carriers of the rare gain-of-function mutation of the gene encoding AMPKγ3 subunit, PRKAG3 R225W.

Methods

Aspects of fuel metabolism were studied in vitro in myocytes isolated from vastus lateralis of PRKAG3 R225W carriers and matched control participants. In vivo, muscular strength and fatigue were evaluated by isokinetic dynamometer and surface electromyography, respectively. Glucose uptake in exercising quadriceps was determined using [18F]fluorodeoxyglucose and positron emission tomography.

Results

Myotubes from PRKAG3 R225W carriers had threefold higher mitochondrial content (p < 0.01) and oxidative capacity, higher leak-dependent respiration (1.6-fold, p < 0.05), higher basal glucose uptake (twofold, p < 0.01) and higher glycogen synthesis rates (twofold, p < 0.05) than control myotubes. They also had higher levels of intracellular glycogen (p < 0.01) and a trend for lower intramuscular triacylglycerol stores. R225W carriers showed remarkable resistance to muscular fatigue and a trend for increased glucose uptake in exercising muscle in vivo.

Conclusions/interpretation

Through the enhancement of skeletal muscle glucose uptake and increased mitochondrial content, the R225W mutation may significantly enhance exercise performance. These findings are also consistent with the hypothesis that the γ3 subunit of AMPK is a promising tissue-specific target for the treatment of type 2 diabetes mellitus, a condition in which glucose uptake and mitochondrial function are impaired.
Appendix
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Metadata
Title
Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes
Authors
S. A. Crawford
S. R. Costford
C. Aguer
S. C. Thomas
R. A. deKemp
J. N. DaSilva
D. Lafontaine
M. Kendall
R. Dent
R. S. B. Beanlands
R. McPherson
M.-E. Harper
Publication date
01-09-2010
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 9/2010
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-010-1788-7

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