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)

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    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 languageEnglish
    Pages (from-to)360-369
    Number of pages10
    JournalDiabetes
    Volume64
    Issue number2
    Early online date22 Oct 2014
    DOIs
    Publication statusPublished - Feb 2015

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    Pirkmajer, S., Kulkarni, S. S., Tom, R. Z., Ross, F. A., Hawley, S. A., Hardie, D. G., Zierath, J. R., & Chibalin, A. V. (2015). Methotrexate promotes glucose uptake and lipid oxidation in skeletal muscle via AMPK activation. Diabetes, 64(2), 360-369. https://doi.org/10.2337/db14-0508