Abstract
The process of Schwann cells (SCs) forming a sheath around axons is termed as myelination, which plays a pivotal role for proper physiological function in the peripheral nervous system (PNS). The molecular mechanisms regulating SC myelination in the PNS remain to be elucidated. Here, we show that AMP-activated protein kinase (AMPK) in sciatic nerves was gradually decreased during the PNS myelination process. Pharmacological interventions showed that activation of AMPK by AICAR attenuated myelin gene expression in SCs, whereas inhibition of AMPK by Compound C (ComC) or AMPKα1 knockdown stimulated myelin gene expression. Following experiments revealed that c-Jun, a negative modulator of PNS myelination, was activated by AMPK in SCs. The application of ComC in newborn rats markedly downregulated c-Jun expression in sciatic nerves. The lipid and protein synthesis in sciatic nerves was greatly potentiated by ComC. As a consequence, myelin gene expression in sciatic nerves, as well as myelin sheath thickness, were promoted in the ComC-treated rats. All together, our data identify that AMPK is an important negative regulator of Schwann cell myelination in the PNS, and this regulation role may rely on c-Jun activation.
Similar content being viewed by others
References
Jessen KR, Mirsky R (2008) Negative regulation of myelination: relevance for development, injury, and demyelinating disease. Glia 56(14):1552–1565. doi:10.1002/glia.20761
Kidd GJ, Ohno N, Trapp BD (2013) Biology of Schwann cells. Handb Clin Neurol 115:55–79. doi:10.1016/B978-0-444-52902-2.00005-9
Norton WT, Poduslo SE (1973) Myelination in rat brain: method of myelin isolation. J Neurochem 21(4):749–757
Pooya S, Liu X, Kumar VB, Anderson J, Imai F, Zhang W, Ciraolo G, Ratner N, Setchell KD, Yutaka Y, Jankowski MP, Dasgupta B (2014) The tumour suppressor LKB1 regulates myelination through mitochondrial metabolism. Nat Commun 5:4993. doi:10.1038/ncomms5993
Norrmen C, Figlia G, Lebrun-Julien F, Pereira JA, Trotzmuller M, Kofeler HC, Rantanen V, Wessig C, van Deijk AL, Smit AB, Verheijen MH, Ruegg MA, Hall MN, Suter U (2014) mTORC1 controls PNS myelination along the mTORC1-RXRgamma-SREBP-lipid biosynthesis axis in Schwann cells. Cell Rep 9(2):646–660. doi:10.1016/j.celrep.2014.09.001
Trimarco A, Forese MG, Alfieri V, Lucente A, Brambilla P, Dina G, Pieragostino D, Sacchetta P, Urade Y, Boizet-Bonhoure B, Martinelli Boneschi F, Quattrini A, Taveggia C (2014) Prostaglandin D2 synthase/GPR44: a signaling axis in PNS myelination. Nat Neurosci 17(12):1682–1692. doi:10.1038/nn.3857
Narayanan SP, Flores AI, Wang F, Macklin WB (2009) Akt signals through the mammalian target of rapamycin pathway to regulate CNS myelination. J Neurosci 29(21):6860–6870. doi:10.1523/JNEUROSCI.0232-09.2009
Burkewitz K, Zhang Y, Mair WB (2014) AMPK at the nexus of energetics and aging. Cell Metab 20(1):10–25. doi:10.1016/j.cmet.2014.03.002
Hardie DG, Ross FA, Hawley SA (2012) AMP-activated protein kinase: a target for drugs both ancient and modern. Chem Biol 19(10):1222–1236. doi:10.1016/j.chembiol.2012.08.019
Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13(4):251–262. doi:10.1038/nrm3311
Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M (2011) AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 13(4):376–388. doi:10.1016/j.cmet.2011.03.009
Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N (2007) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67(22):10804–10812. doi:10.1158/0008-5472.CAN-07-2310
Yuan H, Zhang J, Liu H, Li Z (2013) The protective effects of resveratrol on Schwann cells with toxicity induced by ethanol in vitro. Neurochem Int 63(3):146–153. doi:10.1016/j.neuint.2013.05.011
Ma J, Liu J, Yu H, Chen Y, Wang Q, Xiang L (2015) Effect of metformin on Schwann cells under hypoxia condition. Int J Clin Exp Pathol 8(6):6748–6755
Haastert-Talini K (2012) Culture and proliferation of highly purified adult Schwann cells from rat, dog, and man. Methods Mol Biol 846:189–200. doi:10.1007/978-1-61779-536-7_17
Li S, Wang X, Gu Y, Chen C, Wang Y, Liu J, Hu W, Yu B, Wang Y, Ding F, Liu Y, Gu X (2015) Let-7 microRNAs regenerate peripheral nerve regeneration by targeting nerve growth factor. Mol Ther: J Am Soc Gene Ther 23(3):423–433. doi:10.1038/mt.2014.220
Sun C, Wang M, Liu X, Luo L, Li K, Zhang S, Wang Y, Yang Y, Ding F, Gu X (2014) PCAF improves glucose homeostasis by suppressing the gluconeogenic activity of PGC-1alpha. Cell Rep 9(6):2250–2262. doi:10.1016/j.celrep.2014.11.029
Parkinson DB, Bhaskaran A, Arthur-Farraj P, Noon LA, Woodhoo A, Lloyd AC, Feltri ML, Wrabetz L, Behrens A, Mirsky R, Jessen KR (2008) c-Jun is a negative regulator of myelination. J Cell Biol 181(4):625–637. doi:10.1083/jcb.200803013
Yang DP, Kim J, Syed N, Tung YJ, Bhaskaran A, Mindos T, Mirsky R, Jessen KR, Maurel P, Parkinson DB, Kim HA (2012) p38 MAPK activation promotes denervated Schwann cell phenotype and functions as a negative regulator of Schwann cell differentiation and myelination. J Neurosci 32(21):7158–7168. doi:10.1523/JNEUROSCI.5812-11.2012
Xiao J, Ferner AH, Wong AW, Denham M, Kilpatrick TJ, Murray SS (2012) Extracellular signal-regulated kinase 1/2 signaling promotes oligodendrocyte myelination in vitro. J Neurochem 122(6):1167–1180. doi:10.1111/j.1471-4159.2012.07871.x
Li H, Min Q, Ouyang C, Lee J, He C, Zou MH, Xie Z (2014) AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response. Biochim Biophys Acta 1842(9):1844–1854. doi:10.1016/j.bbadis.2014.07.002
Verheijen MH, Camargo N, Verdier V, Nadra K, de Preux Charles AS, Medard JJ, Luoma A, Crowther M, Inouye H, Shimano H, Chen S, Brouwers JF, Helms JB, Feltri ML, Wrabetz L, Kirschner D, Chrast R, Smit AB (2009) SCAP is required for timely and proper myelin membrane synthesis. Proc Natl Acad Sci U S A 106(50):21383–21388. doi:10.1073/pnas.0905633106
Yu T, Lieberman AP (2013) Npc1 acting in neurons and glia is essential for the formation and maintenance of CNS myelin. PLoS Genet 9(4), e1003462. doi:10.1371/journal.pgen.1003462
Salt IP, Johnson G, Ashcroft SJ, Hardie DG (1998) AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic beta cells, and may regulate insulin release. Biochem J 335(Pt 3):533–539
Ai H, Ihlemann J, Hellsten Y, Lauritzen HP, Hardie DG, Galbo H, Ploug T (2002) Effect of fiber type and nutritional state on AICAR- and contraction-stimulated glucose transport in rat muscle. Am J Physiol Endocrinol Metab 282(6):E1291–E1300. doi:10.1152/ajpendo.00167.2001
Turnley AM, Stapleton D, Mann RJ, Witters LA, Kemp BE, Bartlett PF (1999) Cellular distribution and developmental expression of AMP-activated protein kinase isoforms in mouse central nervous system. J Neurochem 72(4):1707–1716
Ruderman NB, Carling D, Prentki M, Cacicedo JM (2013) AMPK, insulin resistance, and the metabolic syndrome. J Clin Investig 123(7):2764–2772. doi:10.1172/JCI67227
Dasgupta B, Milbrandt J (2009) AMP-activated protein kinase phosphorylates retinoblastoma protein to control mammalian brain development. Dev Cell 16(2):256–270. doi:10.1016/j.devcel.2009.01.005
Williams T, Courchet J, Viollet B, Brenman JE, Polleux F (2011) AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress. Proc Natl Acad Sci U S A 108(14):5849–5854. doi:10.1073/pnas.1013660108
Wakita S, Izumi Y, Nakai T, Adachi K, Takada-Takatori Y, Kume T, Akaike A (2014) Staurosporine induces dopaminergic neurite outgrowth through AMP-activated protein kinase/mammalian target of rapamycin signaling pathway. Neuropharmacology 77:39–48. doi:10.1016/j.neuropharm.2013.09.012
Beirowski B, Babetto E, Golden JP, Chen YJ, Yang K, Gross RW, Patti GJ, Milbrandt J (2014) Metabolic regulator LKB1 is crucial for Schwann cell-mediated axon maintenance. Nat Neurosci 17(10):1351–1361. doi:10.1038/nn.3809
Mechta-Grigoriou F, Gerald D, Yaniv M (2001) The mammalian Jun proteins: redundancy and specificity. Oncogene 20(19):2378–2389. doi:10.1038/sj.onc.1204381
Parkinson DB, Dong Z, Bunting H, Whitfield J, Meier C, Marie H, Mirsky R, Jessen KR (2001) Transforming growth factor beta (TGFbeta) mediates Schwann cell death in vitro and in vivo: examination of c-Jun activation, interactions with survival signals, and the relationship of TGFbeta-mediated death to Schwann cell differentiation. J Neurosci : Off J Soc Neurosci 21(21):8572–8585
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (31271260, 81471037), the Basic Research Program of Jiangsu Education Department (14KJA180006), the Ph.D. Program Foundation of Ministry of Education of China (20110091120029), and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
All of the animal protocols were approved by the Animal Care and Use Committee of Nantong University and the Jiangsu Province Animal Care Ethics Committee. The procedures for sciatic nerve injury model in rats were carried out in accordance with the approved guidelines.
Conflict of Interest
The authors declare that they have no competing interests.
Additional information
Xiaoyu Liu and Su Peng contributed equally to this work.
Rights and permissions
About this article
Cite this article
Liu, X., Peng, S., Zhao, Y. et al. AMPK Negatively Regulates Peripheral Myelination via Activation of c-Jun. Mol Neurobiol 54, 3554–3564 (2017). https://doi.org/10.1007/s12035-016-9913-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-016-9913-3