Methotrexate promotes glucose uptake and lipid oxidation in skeletal muscle via AMPK activation

Sergej Pirkmajer; Sameer S. Kulkarni; Robby Z. Tom; Fiona A. Ross; Simon A. Hawley; D. Grahame Hardie; Juleen R. Zierath; Alexander V. Chibalin

doi:10.2337/db14-0508

Methotrexate promotes glucose uptake and lipid oxidation in skeletal muscle via AMPK activation

Sergej Pirkmajer, Sameer S. Kulkarni, Robby Z. Tom, Fiona A. Ross, Simon A. Hawley, D. Grahame Hardie, Juleen R. Zierath, Alexander V. Chibalin (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

65 Citations (Scopus)

197 Downloads (Pure)

Abstract

Methotrexate (MTX) is a widely used anticancer and antirheumatic drug that has been postulated to protect against metabolic risk factors associated with type 2 diabetes, although the mechanism remains unknown. MTX inhibits 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) and thereby slows the metabolism of 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranosyl-5'-monophosphate (ZMP) and its precursor AICAR, which is a pharmacological AMPK activator. We explored whether MTX promotes AMPK activation in cultured myotubes and isolated skeletal muscle. We found MTX markedly reduced the threshold for AICAR-induced AMPK activation and potentiated glucose uptake and lipid oxidation. Gene silencing of the MTX target ATIC activated AMPK and stimulated lipid oxidation in cultured myotubes. Furthermore, MTX activated AMPK in wild-type HEK-293 cells. These effects were abolished in skeletal muscle lacking the muscle-specific, ZMP-sensitive AMPK-?3 subunit and in HEK-293 cells expressing a ZMP-insensitive mutant AMPK-?2 subunit. Collectively, our findings underscore a role for AMPK as a direct molecular link between MTX and energy metabolism in skeletal muscle. Cotherapy with AICAR and MTX could represent a novel strategy to treat metabolic disorders and overcome current limitations of AICAR monotherapy.

Original language	English
Pages (from-to)	360-369
Number of pages	10
Journal	Diabetes
Volume	64
Issue number	2
Early online date	22 Oct 2014
DOIs	https://doi.org/10.2337/db14-0508
Publication status	Published - Feb 2015

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.2337/db14-0508

Author accepted manuscript
This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http://diabetes.diabetesjournals.org.
Accepted author manuscript, 505 KB

Rab Detection Initiative (Joint with Stanford School of Medicine, Max Plank Institute, Neuroscience Research Australia and Parkinsons Institute California)
Alessi, D. (Investigator) & Davies, P. (Investigator)
1/08/16 → 31/07/21
Project: Research
Non-canonical Pathways for Regulation of AMPK (Senior Investigator Award)
Hardie, G. (Investigator)
1/04/12 → 30/09/17
Project: Research

Cite this

@article{df551f037ebe42caa5aabb422115c520,

title = "Methotrexate promotes glucose uptake and lipid oxidation in skeletal muscle via AMPK activation",

abstract = "Methotrexate (MTX) is a widely used anticancer and antirheumatic drug that has been postulated to protect against metabolic risk factors associated with type 2 diabetes, although the mechanism remains unknown. MTX inhibits 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) and thereby slows the metabolism of 5-aminoimidazole-4-carboxamide-1-{\ss}-d-ribofuranosyl-5'-monophosphate (ZMP) and its precursor AICAR, which is a pharmacological AMPK activator. We explored whether MTX promotes AMPK activation in cultured myotubes and isolated skeletal muscle. We found MTX markedly reduced the threshold for AICAR-induced AMPK activation and potentiated glucose uptake and lipid oxidation. Gene silencing of the MTX target ATIC activated AMPK and stimulated lipid oxidation in cultured myotubes. Furthermore, MTX activated AMPK in wild-type HEK-293 cells. These effects were abolished in skeletal muscle lacking the muscle-specific, ZMP-sensitive AMPK-?3 subunit and in HEK-293 cells expressing a ZMP-insensitive mutant AMPK-?2 subunit. Collectively, our findings underscore a role for AMPK as a direct molecular link between MTX and energy metabolism in skeletal muscle. Cotherapy with AICAR and MTX could represent a novel strategy to treat metabolic disorders and overcome current limitations of AICAR monotherapy.",

author = "Sergej Pirkmajer and Kulkarni, {Sameer S.} and Tom, {Robby Z.} and Ross, {Fiona A.} and Hawley, {Simon A.} and Hardie, {D. Grahame} and Zierath, {Juleen R.} and Chibalin, {Alexander V.}",

note = "{\textcopyright} 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. This study was supported with funding from the European Research Council Ideas Program (ICEBERG, ERC-2008-AdG23285), the Swedish Research Council, the Swedish Diabetes Association, the Strategic Research Foundation, the Novo Nordisk Research Foundation, the Commission of the European Communities (Contract No. LSHM-CT-2004-005272 EXGENESIS), and the Strategic Research Programme in Diabetes at Karolinska Institutet. Studies in the Hardie laboratory are supported by a Senior Investigator Award (097726) from the Wellcome Trust and by a Programme Grant (C37030/A15101) from Cancer Research UK. S.P. was supported by the Slovenian Research Agency (grant P3-0043) and the Erasmus Lifelong Learning Programme.",

year = "2015",

month = feb,

doi = "10.2337/db14-0508",

language = "English",

volume = "64",

pages = "360--369",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "2",

}

TY - JOUR

T1 - Methotrexate promotes glucose uptake and lipid oxidation in skeletal muscle via AMPK activation

AU - Pirkmajer, Sergej

AU - Kulkarni, Sameer S.

AU - Tom, Robby Z.

AU - Ross, Fiona A.

AU - Hawley, Simon A.

AU - Hardie, D. Grahame

AU - Zierath, Juleen R.

AU - Chibalin, Alexander V.

N1 - © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. This study was supported with funding from the European Research Council Ideas Program (ICEBERG, ERC-2008-AdG23285), the Swedish Research Council, the Swedish Diabetes Association, the Strategic Research Foundation, the Novo Nordisk Research Foundation, the Commission of the European Communities (Contract No. LSHM-CT-2004-005272 EXGENESIS), and the Strategic Research Programme in Diabetes at Karolinska Institutet. Studies in the Hardie laboratory are supported by a Senior Investigator Award (097726) from the Wellcome Trust and by a Programme Grant (C37030/A15101) from Cancer Research UK. S.P. was supported by the Slovenian Research Agency (grant P3-0043) and the Erasmus Lifelong Learning Programme.

PY - 2015/2

Y1 - 2015/2

N2 - Methotrexate (MTX) is a widely used anticancer and antirheumatic drug that has been postulated to protect against metabolic risk factors associated with type 2 diabetes, although the mechanism remains unknown. MTX inhibits 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) and thereby slows the metabolism of 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranosyl-5'-monophosphate (ZMP) and its precursor AICAR, which is a pharmacological AMPK activator. We explored whether MTX promotes AMPK activation in cultured myotubes and isolated skeletal muscle. We found MTX markedly reduced the threshold for AICAR-induced AMPK activation and potentiated glucose uptake and lipid oxidation. Gene silencing of the MTX target ATIC activated AMPK and stimulated lipid oxidation in cultured myotubes. Furthermore, MTX activated AMPK in wild-type HEK-293 cells. These effects were abolished in skeletal muscle lacking the muscle-specific, ZMP-sensitive AMPK-?3 subunit and in HEK-293 cells expressing a ZMP-insensitive mutant AMPK-?2 subunit. Collectively, our findings underscore a role for AMPK as a direct molecular link between MTX and energy metabolism in skeletal muscle. Cotherapy with AICAR and MTX could represent a novel strategy to treat metabolic disorders and overcome current limitations of AICAR monotherapy.

AB - Methotrexate (MTX) is a widely used anticancer and antirheumatic drug that has been postulated to protect against metabolic risk factors associated with type 2 diabetes, although the mechanism remains unknown. MTX inhibits 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) and thereby slows the metabolism of 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranosyl-5'-monophosphate (ZMP) and its precursor AICAR, which is a pharmacological AMPK activator. We explored whether MTX promotes AMPK activation in cultured myotubes and isolated skeletal muscle. We found MTX markedly reduced the threshold for AICAR-induced AMPK activation and potentiated glucose uptake and lipid oxidation. Gene silencing of the MTX target ATIC activated AMPK and stimulated lipid oxidation in cultured myotubes. Furthermore, MTX activated AMPK in wild-type HEK-293 cells. These effects were abolished in skeletal muscle lacking the muscle-specific, ZMP-sensitive AMPK-?3 subunit and in HEK-293 cells expressing a ZMP-insensitive mutant AMPK-?2 subunit. Collectively, our findings underscore a role for AMPK as a direct molecular link between MTX and energy metabolism in skeletal muscle. Cotherapy with AICAR and MTX could represent a novel strategy to treat metabolic disorders and overcome current limitations of AICAR monotherapy.

U2 - 10.2337/db14-0508

DO - 10.2337/db14-0508

M3 - Article

C2 - 25338814

SN - 0012-1797

VL - 64

SP - 360

EP - 369

JO - Diabetes

JF - Diabetes

IS - 2

ER -

Methotrexate promotes glucose uptake and lipid oxidation in skeletal muscle via AMPK activation

Abstract

UN SDGs

Access to Document

Fingerprint

Projects

Rab Detection Initiative (Joint with Stanford School of Medicine, Max Plank Institute, Neuroscience Research Australia and Parkinsons Institute California)

Non-canonical Pathways for Regulation of AMPK (Senior Investigator Award)

Cite this