AMPK-independent pathways regulate skeletal muscle fatty acid oxidation

Nicolas L Dzamko, Jonathan D Schertzer, James Ryall, Rohan Steel, S Lance Macaulay, Sheena Wee, Z-P Chen, Belinda J Michell, Johathan S Oakhill, Matthew James Watt, Sebastian B Jorgensen, Gordon S Lynch, Bruce Ernest Kemp, Gregory R Steinberg

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The activation of AMP-activated protein kinase (AMPK) and phosphorylation/inhibition of acetyl-CoA carboxylase 2 (ACC2) is believed to be the principal pathway regulating fatty acid oxidation. However, during muscle contraction/exercise AMPK activity and ACC phosphorylation does not always correlate with rates of fatty acid oxidation. To address this issue we have investigated the requirement for skeletal muscle AMPK in controlling aminoimidazole-4-carboxymide-1-lower case Greek beta-D-ribofuranoside (AICAR) and contraction-stimulated fatty acid oxidation utilizing transgenic mice expressing a muscle-specific kinase dead (KD) AMPK alpha2 ex vivo, in situ and in vivo during treadmill exercise. In wildtype mice, AICAR and contraction increased AMPK alpha2 and alpha1 activity. However, despite no activation of AMPK in KD mice, ACC2 phosphorylation at the AMPK site (S221) and rates of fatty acid oxidation were comparable between genotypes. Similar results were also obtained during in situ muscle contraction and during endurance treadmill exercise. These studies suggested the presence of an alternative ACC2 kinase(s). Using a phosphoproteomics based approach we identified 18 protein kinases whose phosphorylation was increased by greater than 25 in contracted KD relative WT muscle. From this list of kinases we utilized bioinformatics to predict that extracellular regulated protein-serine kinase (ERK 1/2), inhibitor of NF-kappa-B protein-serine kinase beta (IKKbeta) and protein kinase D (PKD) may phosphorylate ACC2 at S221. In vitro phosphorylation assays demonstrate that only AMPK is able to phosphorylate ACC2 S221. These data demonstrate that AMPK is not essential for the regulation of fatty acid oxidation by AICAR or muscle contraction.
Original languageEnglish
Pages (from-to)5819 - 5831
Number of pages13
JournalThe Journal of Physiology
Issue number23
Publication statusPublished - 2008

Cite this

Dzamko, N. L., Schertzer, J. D., Ryall, J., Steel, R., Macaulay, S. L., Wee, S., Chen, Z-P., Michell, B. J., Oakhill, J. S., Watt, M. J., Jorgensen, S. B., Lynch, G. S., Kemp, B. E., & Steinberg, G. R. (2008). AMPK-independent pathways regulate skeletal muscle fatty acid oxidation. The Journal of Physiology, 586(23), 5819 - 5831.