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Essential Roles of Lactate in Müller Cell Survival and Function

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Abstract

Müller cells are pivotal in sustaining retinal ganglion cells, and an intact energy metabolism is essential for upholding Müller cell functions. The present study aimed to investigate the impact of lactate on Müller cell survival and function. Primary mice Müller cells and human Müller cell lines (MIO-M1) were treated with or without lactate (10 or 20 mM) for 2 and 24 hours. Simultaneously, Müller cells were incubated with or without 6 mM of glucose. L-lactate exposure increased Müller cell survival independently of the presence of glucose. This effect was abolished by the addition of the monocarboxylate inhibitor 4-cinnamic acid to the treatment media, whereas survival continued to increase in response to addition of D-lactate during glucose restriction. ATP levels decreased over time in MIO-M1 cells and remained stable over time in primary Müller cells. Lactate was preferably metabolized in MIO-M1 cells compared to glucose, and 10 mM of L-Lactate exposure prevented complete glycogen depletion in MIO-M1 cells. Glutamate uptake increased after 2 hours and decreased after 24 hours in glucose-restricted Müller cells compared to cells with glucose supplement. The addition of 10 mM of lactate to the treatment media increased glutamate uptake in glucose supplemented and restricted cells. In conclusion, lactate is a key component in maintaining Müller cell survival and function. Hence, lactate administration may be of great future interest, ultimately leading to novel therapies to rescue retinal ganglion cells.

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References

  1. Goodwin ML, Harris JE, Hernández A, Gladden LB (2007) Blood lactate measurements and analysis during exercise: a guide for clinicians. J Diabetes Sci Technol 1:558–569

    Article  Google Scholar 

  2. Mosienko V, Teschemacher AG, Kasparov S (2015) Is L-lactate a novel signaling molecule in the brain? J Cereb Blood Flow Metab 35:1069–1075. https://doi.org/10.1038/jcbfm.2015.77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schurr A, Payne RS (2007) Lactate, not pyruvate, is neuronal aerobic glycolysis end product: an in vitro electrophysiological study. Neuroscience 147:613–619. https://doi.org/10.1016/j.neuroscience.2007.05.002

    Article  CAS  PubMed  Google Scholar 

  4. Schurr A (2014) Cerebral glycolysis: a century of persistent misunderstanding and misconception. Front Neurosci 8:360. https://doi.org/10.3389/fnins.2014.00360

    Article  PubMed  PubMed Central  Google Scholar 

  5. Schurr A, Gozal E (2015) Glycolysis at 75: is it time to tweak the first elucidated metabolic pathway in history? Front Neurosci 9:170. https://doi.org/10.3389/fnins.2015.00170

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ros J, Pecinska N, Alessandri B, Landolt H, Fillenz M (2001) Lactate reduces glutamate-induced neurotoxicity in rat cortex. J Neurosci Res 66:790–794

    Article  CAS  Google Scholar 

  7. Cureton EL, Kwan RO, Dozier KC, Sadjadi J, Pal JD, Victorino GP (2010) A different view of lactate in trauma patients: protecting the injured brain. J Surg Res 159:468–473. https://doi.org/10.1016/j.jss.2009.04.020

    Article  CAS  PubMed  Google Scholar 

  8. Rice AC, Zsoldos R, Chen T, Wilson MS, Alessandri B, Hamm RJ et al (2002) Lactate administration attenuates cognitive deficits following traumatic brain injury. Brain Res 928:156–159

    Article  CAS  Google Scholar 

  9. Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM (2011) Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144:810–823. https://doi.org/10.1016/j.cell.2011.02.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Magistretti PJ, Allaman I (2018) Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci 19:235–249. https://doi.org/10.1038/nrn.2018.19

    Article  CAS  PubMed  Google Scholar 

  11. Taher M, Leen WG, Wevers RA, Willemsen MA (2016) Lactate and its many faces. Eur J Paediatr Neurol 20:3–10. https://doi.org/10.1016/j.ejpn.2015.09.008

    Article  PubMed  Google Scholar 

  12. Dienel GA (2012) Brain lactate metabolism: the discoveries and the controversies. J Cereb Blood Flow Metab 32:1107–1138. https://doi.org/10.1038/jcbfm.2011.175

    Article  CAS  PubMed  Google Scholar 

  13. Adler AJ, Southwick RE (1992) Distribution of glucose and lactate in the interphotoreceptor matrix. Ophthalmic Res 24:243–252

    Article  CAS  Google Scholar 

  14. Wang L, Törnquist P, Bill A (1997) Glucose metabolism in pig outer retina in light and darkness. Acta Physiol Scand 160:75–81. https://doi.org/10.1046/j.1365-201X.1997.00030.x.

    Article  CAS  PubMed  Google Scholar 

  15. Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A (2012) The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 31:152–181. https://doi.org/10.1016/j.preteyeres.2011.11.002

    Article  CAS  Google Scholar 

  16. Rodrigues EB, Urias MG, Penha FM, Badaró E, Novais E, Meirelles R, Farah ME (2015) Diabetes induces changes in neuroretina before retinal vessels: a spectral-domain optical coherence tomography study. Int J Retina Vitreous 1:4. https://doi.org/10.1186/s40942-015-0001-z

    Article  PubMed  PubMed Central  Google Scholar 

  17. Sohn EH, van Dijk HW, Jiao C, Kok PHB, Jeong W, Demirkaya N et al (2016) Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus. PNAS 113:E2655–E2664. https://doi.org/10.1073/pnas.1522014113

    Article  CAS  PubMed  Google Scholar 

  18. Kawasaki A, Otori Y, Barnstable C (2000) Müller cell protection of rat retinal ganglion cells from glutamate and nitric oxide neurotoxicity. Invest Ophthalmol Vis Sci 41:3444–3450

    CAS  PubMed  Google Scholar 

  19. Skytt DM, Toft-Kehler AK, Brændstrup CT, Cejvanovic S, Gurubaran IS, Bergersen LH, Kolko M (2016) Glia-neuron interactions in the retina can be studied in cocultures of Müller cells and retinal ganglion cells. Biomed Res Int 2016:1–10. https://doi.org/10.1155/2016/1087647.

    Article  Google Scholar 

  20. Schultz R, Krug M, Precht M, Wohl SG, Witte OW, Schmeer C (2018) Frataxin overexpression in Müller cells protects retinal ganglion cells in a mouse model of ischemia/reperfusion injury in vivo. Sci Rep 8:4846. https://doi.org/10.1038/s41598-018-22887-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bringmann A, Iandiev I, Pannicke T, Wurm A, Hollborn M, Wiedemann P, Osborne NN, Reichenbach A (2009) Cellular signaling and factors involved in Müller cell gliosis: neuroprotective and detrimental effects. Prog Retin Eye Res 28:423–451. https://doi.org/10.1016/j.preteyeres.2009.07.001

    Article  CAS  Google Scholar 

  22. Bringmann A, Grosche A, Pannicke T, Reichenbach A (2013) GABA and glutamate uptake and metabolism in retinal glial (Müller) cells. Front Endocrinol (Lausanne) 4:48. https://doi.org/10.3389/fendo.2013.00048

    Article  CAS  Google Scholar 

  23. Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov S et al (2006) Müller cells in the healthy and diseased retina. Prog Retin Eye Res 25:397–424. https://doi.org/10.1016/j.preteyeres.2006.05.003

    Article  CAS  Google Scholar 

  24. Bringmann A, Pannicke T, Biedermann B, Francke M, Iandiev I, Grosche J, Wiedemann P, Albrecht J et al (2009) Role of retinal glial cells in neurotransmitter uptake and metabolism. Neurochem Int 54:143–160. https://doi.org/10.1016/j.neuint.2008.10.014

    Article  CAS  Google Scholar 

  25. Bringmann A, Wiedemann P (2012) Müller glial cells in retinal disease. Ophthalmologica 227:1–19. https://doi.org/10.1159/000328979.

    Article  PubMed  Google Scholar 

  26. Winkler BS, Arnold MJ, Brassell MA, Puro DG (2000) Energy metabolism in human retinal Müller. Cell 41:3183–3190

    CAS  Google Scholar 

  27. Winkler BS, Starnes CA, Sauer MW, Firouzgan Z, Chen S-C (2004) Cultured retinal neuronal cells and Müller cells both show net production of lactate. Neurochem Int 45:311–320. https://doi.org/10.1016/j.neuint.2003.08.017

    Article  CAS  PubMed  Google Scholar 

  28. Toft-Kehler AK, Skytt DM, Svare A, Lefevere E, Van Hove I, Moons L et al (2017) Mitochondrial function in Müller cells—does it matter? Mitochondrion 36:43–51. https://doi.org/10.1016/j.mito.2017.02.002

    Article  CAS  PubMed  Google Scholar 

  29. Lindsay KJ, Du J, Sloat SR, Contreras L, Linton JD, Turner SJ et al (2014) Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina. Proc Natl Acad Sci U S A 111:15579–15584. https://doi.org/10.1073/pnas.1412441111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Poitry-Yamate CL, Poitry S, Tsacopoulos M (1995) Lactate released by Müller glial cells is metabolized by photoreceptors from mammalian retina. J Neurosci 15:5179–5191

    Article  CAS  Google Scholar 

  31. Winkler BS, Sauer MW, Starnes CA (2003) Modulation of the Pasteur effect in retinal cells: implications for understanding compensatory metabolic mechanisms. Exp Eye Res 76:715–723

    Article  CAS  Google Scholar 

  32. Toft-Kehler AK, Gurubaran IS, Desler C, Rasmussen LJ, Skytt DM, Kolko M (2016) Oxidative stress-induced dysfunction of Müller cells during starvation. Invest Ophthalmol Vis Sci 57:2721–2728. https://doi.org/10.1167/iovs.16-19275

    Article  CAS  PubMed  Google Scholar 

  33. Vohra R, Gurubaran IS, Henriksen U, Bergersen LH, Rasmussen LJ, Desler C, Skytt DM, Kolko M (2017) Disturbed mitochondrial function restricts glutamate uptake in the human Müller glia cell line, MIO-M1. Mitochondrion 36:52–59. https://doi.org/10.1016/j.mito.2017.02.003.

    Article  CAS  PubMed  Google Scholar 

  34. Flammer J, Orgül S, Costa VP, Orzalesi N, Krieglstein GK, Serra LM, Renard JP, Stefánsson E (2002) The impact of ocular blood flow in glaucoma. Prog Retin Eye Res 21:359–393. https://doi.org/10.1016/S1350-9462(02)00008-3

    Article  PubMed  Google Scholar 

  35. Abegão Pinto L, Willekens K, Van Keer K, Shibesh A, Molenberghs G, Vandewalle E et al (2016) Ocular blood flow in glaucoma—the Leuven Eye Study. Acta Ophthalmol 94:592–598. https://doi.org/10.1111/aos.12962

    Article  PubMed  Google Scholar 

  36. Shiga Y, Kunikata H, Aizawa N, Kiyota N, Maiya Y, Yokoyama Y, Omodaka K, Takahashi H et al (2016) Optic nerve head blood flow, as measured by laser speckle flowgraphy, is significantly reduced in preperimetric glaucoma. Curr Eye Res 41:1447–1453. https://doi.org/10.3109/02713683.2015.1127974

    Article  Google Scholar 

  37. Limb GA, Salt TE, Munro PMG, Moss SE, Khaw PT (2002) In vitro characterization of a spontaneously immortalized human Müller cell line (MIO-M1). Invest Ophthalmol Vis Sci 43:864–869

    PubMed  Google Scholar 

  38. Aldana BI, Zhang Y, Lihme MF, Bak LK, Nielsen JE, Holst B, Hyttel P, Freude KK et al (2017) Characterization of energy and neurotransmitter metabolism in cortical glutamatergic neurons derived from human induced pluripotent stem cells: a novel approach to study metabolism in human neurons. Neurochem Int 106:48–61. https://doi.org/10.1016/j.neuint.2017.02.010

    Article  CAS  Google Scholar 

  39. Toft-Kehler AK, Skytt DM, Poulsen KA, Brændstrup CT, Gegelashvili G, Waagepetersen H, Kolko M (2014) Limited energy supply in Müller cells alters glutamate uptake. Neurochem Res 39:941–949. https://doi.org/10.1007/s11064-014-1289-z

    Article  CAS  PubMed  Google Scholar 

  40. Waagepetersen HS, Bakken IJ, Larsson OM, Sonnewald U, Schousboe A (1998) Comparison of lactate and glucose metabolism in cultured neocortical neurons and astrocytes using 13C-NMR spectroscopy. Dev Neurosci 20:310–320

    Article  CAS  Google Scholar 

  41. Bak LK, Walls AB (2018) CrossTalk opposing view: lack of evidence supporting an astrocyte-to-neuron lactate shuttle coupling neuronal activity to glucose utilisation in the brain. J Physiol Lond 596:351–353. https://doi.org/10.1113/JP274945

    Article  CAS  PubMed  Google Scholar 

  42. Wang L, Kondo M, Bill A (1997) Glucose metabolism in cat outer retina. Effects of light and hyperoxia. Invest Ophthalmol Vis Sci 38:48–55

    CAS  PubMed  Google Scholar 

  43. Brown AM, Wender R, Ransom BR (2001) Metabolic substrates other than glucose support axon function in central white matter. J Neurosci Res 66:839–843. https://doi.org/10.1002/jnr.10081

    Article  CAS  PubMed  Google Scholar 

  44. Chidlow G, Wood JPM, Graham M, Osborne NN (2005) Expression of monocarboxylate transporters in rat ocular tissues. Am J Physiol, Cell Physiol 288:C416–C428. https://doi.org/10.1152/ajpcell.00037.2004

    Article  CAS  PubMed  Google Scholar 

  45. Kolko M, Vosborg F, Henriksen UL, Hasan-Olive MM, Diget EH, Vohra R, Gurubaran IRS, Gjedde A et al (2016) Lactate transport and receptor actions in retina: potential roles in retinal function and disease. Neurochem Res 41:1229–1236. https://doi.org/10.1007/s11064-015-1792-x

    Article  Google Scholar 

  46. Roland CL, Arumugam T, Deng D, Liu SH, Philip B, Gomez S, Burns WR, Ramachandran V et al (2014) Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Res 74:5301–5310. https://doi.org/10.1158/0008-5472.CAN-14-0319

    Article  CAS  Google Scholar 

  47. Rinholm JE, Hamilton NB, Kessaris N, Richardson WD, Bergersen LH, Attwell D (2011) Regulation of oligodendrocyte development and myelination by glucose and lactate. J Neurosci 31:538–548. https://doi.org/10.1523/JNEUROSCI.3516-10.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Frenzel J, Richter J, Eschrich K (2005) Pyruvate protects glucose-deprived Müller cells from nitric oxide-induced oxidative stress by radical scavenging. Glia 52:276–288. https://doi.org/10.1002/glia.20244

    Article  PubMed  Google Scholar 

  49. Poole RC, Cranmer SL, Halestrap AP, Levi AJ (1990) Substrate and inhibitor specificity of monocarboxylate transport into heart cells and erythrocytes. Further evidence for the existence of two distinct carriers. Biochem J 269:827–829

    Article  CAS  Google Scholar 

  50. Wang X, Poole RC, Halestrap AP, Levi AJ (1993) Characterization of the inhibition by stilbene disulphonates and phloretin of lactate and pyruvate transport into rat and guinea-pig cardiac myocytes suggests the presence of two kinetically distinct carriers in heart cells. Biochem J 290(Pt 1):249–258

    Article  CAS  Google Scholar 

  51. Smith D, Pernet A, Hallett WA, Bingham E, Marsden PK, Amiel SA (2003) Lactate: a preferred fuel for human brain metabolism in vivo. J Cereb Blood Flow Metab 23:658–664. https://doi.org/10.1097/01.WCB.0000063991.19746.11

    Article  CAS  PubMed  Google Scholar 

  52. Bouzier-Sore A-K, Voisin P, Canioni P, Magistretti PJ, Pellerin L (2003) Lactate is a preferential oxidative energy substrate over glucose for neurons in culture. J Cereb Blood Flow Metab 23:1298–1306. https://doi.org/10.1097/01.WCB.0000091761.61714.25

    Article  CAS  PubMed  Google Scholar 

  53. Bergersen LH (2007) Is lactate food for neurons? Comparison of monocarboxylate transporter subtypes in brain and muscle. Neuroscience 145:11–19. https://doi.org/10.1016/j.neuroscience.2006.11.062

    Article  CAS  PubMed  Google Scholar 

  54. van Hall G, Strømstad M, Rasmussen P, Jans O, Zaar M, Gam C et al (2009) Blood lactate is an important energy source for the human brain. J Cereb Blood Flow Metab 29:1121–1129. https://doi.org/10.1038/jcbfm.2009.35

    Article  CAS  PubMed  Google Scholar 

  55. Hertz L, Peng L, Dienel GA (2007) Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J Cereb Blood Flow Metab 27:219–249. https://doi.org/10.1038/sj.jcbfm.9600343

    Article  CAS  PubMed  Google Scholar 

  56. Toft-Kehler AK, Skytt DM, Kolko M (2017) A perspective on the Müller cell-neuron metabolic partnership in the inner retina. Mol Neurobiol. https://doi.org/10.1007/s12035-017-0760-7

    Article  Google Scholar 

  57. Johnson NF (1977) Retinal glycogen content during ischaemia. Albrecht Von Graefes Arch Klin Exp Ophthalmol 203:271–282

    Article  CAS  Google Scholar 

  58. Goldman SS (1990) Evidence that the gluconeogenic pathway is confined to an enriched Müller cell fraction derived from the amphibian retina. Exp Eye Res 50:213–218

    Article  CAS  Google Scholar 

  59. Pfeiffer-Guglielmi B, Francke M, Reichenbach A, Fleckenstein B, Jung G, Hamprecht B (2005) Glycogen phosphorylase isozyme pattern in mammalian retinal Müller (glial) cells and in astrocytes of retina and optic nerve. Glia 49:84–95. https://doi.org/10.1002/glia.20102

    Article  PubMed  Google Scholar 

  60. Swanson RA (1992) Astrocyte glutamate uptake during chemical hypoxia in vitro. Neurosci Lett 147:143–146

    Article  CAS  Google Scholar 

  61. Swanson RA, Chen J, Graham SH (1994) Glucose can fuel glutamate uptake in ischemic brain. J Cereb Blood Flow Metab 14:1–6. https://doi.org/10.1038/jcbfm.1994.1

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank Laboratory Technician Charlotte Taul Brændstrup for skillful assistance to the study. The study was supported by the Michaelsen Foundation, the Velux Foundation, Denmark and Fight for Sight, Denmark.

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Authors and Affiliations

  1. Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen Ø, Denmark

    Rupali Vohra, Blanca I. Aldana, Dorte M. Skytt, Helle Waagepetersen & Miriam Kolko

  2. Faculty of Health and Medical Sciences, Department of Veterinary and Animal Sciences, Section for Anatomy & Biochemistry, University of Copenhagen, Grønnegårdsvej 7, 1870, Frederiksberg C, Denmark

    Kristine Freude

  3. Center of Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen N, Denmark

    Linda H. Bergersen

  4. Brain and Muscle Energy Group, Faculty of Dentistry, Department of Oral Biology, University of Oslo, Sognsvannsveien 10, 0372, Oslo, Norway

    Linda H. Bergersen

  5. Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet-Glostrup, Valdemar Hansens vej 1-23, 2600, Glostrup, Denmark

    Miriam Kolko

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  1. Rupali Vohra
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Correspondence to Miriam Kolko.

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Vohra, R., Aldana, B.I., Skytt, D.M. et al. Essential Roles of Lactate in Müller Cell Survival and Function. Mol Neurobiol 55, 9108–9121 (2018). https://doi.org/10.1007/s12035-018-1056-2

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