Recent studies have demonstrated a new role for Klf10, a Krüppel-like transcription factor, in skeletal muscle, specifically relating to mitochondrial function. Thus, it was of interest to analyze additional tissues that are highly reliant on optimal mitochondrial function such as the cerebellum and to decipher the role of Klf10 in the functional and structural properties of this brain region. In vivo (magnetic resonance imaging and localized spectroscopy, behavior analysis) and in vitro (histology, spectroscopy analysis, enzymatic activity) techniques were applied to comprehensively assess the cerebellum of wild type (WT) and Klf10 knockout (KO) mice. Histology analysis and assessment of locomotion revealed no significant difference in Klf10 KO mice. Diffusion and texture results obtained using MRI revealed structural changes in KO mice characterized as defects in the organization of axons. These modifications may be explained by differences in the levels of specific metabolites (myo-inositol, lactate) within the KO cerebellum. Loss of Klf10 expression also led to changes in mitochondrial activity as reflected by a significant increase in the activity of citrate synthase, complexes I and IV. In summary, this study has provided evidence that Klf10 plays an important role in energy production and mitochondrial function in the cerebellum.
References
[1]
Subramaniam, M., Harris, S.A., Oursler, M.J., Rasmussen, K., Riggs, B.L. and Spelsberg, T.C. (1995) Identification of a Novel TGF-β-Regulated Gene Encoding a Putative Zinc Finger Protein in Human Osteoblasts. Nucleic Acids Research, 23, 4907-4912. https://doi.org/10.1093/nar/23.23.4907
[2]
Bensamoun, S.F., Hawse, J.R., Subramaniam, M., Ilharreborde, B., Bassillais, A., Benhamou, C.L., Fraser, D.G., Oursler, M.J., Amadio, P.C., An, K.-N. and Spelsberg, T.C. (2006) TGFβ Inducible Early Gene-1 Knockout Mice Display Defects in Bone Strength and Microarchitecture. Bone, 39, 1244-1251. https://doi.org/10.1016/j.bone.2006.05.021
Hawse, J.R., Pitel, K.S., Cicek, M., Philbrick, K.A., Gingery, A., Peters, K.D., Syed, F.A., Ingle, J.N., Suman, V.J., Iwaniec, U.T., Turner, R.T., Spelsberg, T.C. and Subramaniam, M. (2014) TGFβ Inducible Early Gene-1 Plays an Important Role in Mediating Estrogen Signaling in the Skeleton. Journal of Bone and Mineral Research, 29, 1206-1216. https://doi.org/10.1002/jbmr.2142
[5]
Rajamannan, N.M., Subramaniam, M., Abraham, T.P., Vasile, V.C., Ackerman, M.J., Monroe, D.G., Chew, T.-L. and Spelsberg, T.C. (2007) TGFβ Inducible Early Gene-1 (TIEG1) and Cardiac Hypertrophy: Discovery and Characterization of a Novel Signaling Pathway. Journal of Cellular Biochemistry, 100, 315-325. https://doi.org/10.1002/jcb.21049
[6]
Cao, Z., Wara, A.K., Icli, B., Sun, X., Packard, R.R.S., Esen, F., Stapleton, C.J., Subramaniam, M., Kretschmer, K., Apostolou, I., Boehmer, H. von, Hansson, G.K., Spelsberg, T.C., Libby, P. and Feinberg, M.W. (2009) Kruppel-Like Factor KLF10 Targets Transforming Growth Factor-β1 to Regulate CD4+CD25-T Cells and T Regulatory Cells. Journal of Biological Chemistry, 284, 24914-24924. https://doi.org/10.1074/jbc.M109.000059
[7]
Wara, A.K., Foo, S., Croce, K., Sun, X., Icli, B., Tesmenitsky, Y., Esen, F., Lee, J.-S., Subramaniam, M., Spelsberg, T.C., Lev, E.I., Leshem-Lev, D., Pande, R.L., Creager, M.A., Rosenzweig, A. and Feinberg, M.W. (2011) TGF-β1 Signaling and Krüppel-Like Factor 10 Regulate Bone Marrow-Derived Proangiogenic Cell Differentiation, Function, and Neovascularization. Blood, 118, 6450-6460. https://doi.org/10.1182/blood-2011-06-363713
[8]
Venuprasad, K., Huang, H., Harada, Y., Elly, C., Subramaniam, M., Spelsberg, T., Su, J. and Liu, Y.-C. (2008) The E3 Ubiquitin Ligase Itch Regulates Expression of Transcription Factor Foxp3 and Airway Inflammation by Enhancing the Function of Transcription Factor TIEG1. Nature Immunology, 9, 245-253. https://doi.org/10.1038/ni1564
[9]
Ruberto, A.A., Gréchez-Cassiau, A., Guérin, S., Martin, L., Revel, J.S., Mehiri, M., Subramaniam, M., Delaunay, F. and Teboul, M. (2021) KLF10 Integrates Circadian Timing and Sugar Signaling to Coordinate Hepatic Metabolism. ELife, 10, e65574. https://doi.org/10.7554/eLife.65574
[10]
Guillaumond, F., Gréchez-Cassiau, A., Subramaniam, M., Brangolo, S., Peteri-Brünback, B., Staels, B., Fiévet, C., Spelsberg, T.C., Delaunay, F. and Teboul, M. (2010) Krüppel-Like Factor KLF10 Is a Link between the Circadian Clock and Metabolism in Liver. Molecular and Cellular Biology, 30, 3059-3070. https://doi.org/10.1128/MCB.01141-09
[11]
Yerges, L.M., Klei, L., Cauley, J.A., Roeder, K., Kammerer, C.M., Ensrud, K.E., Nestlerode, C.S., Lewis, C., Lang, T.F., Barrett-Connor, E., Moffett, S.P., Hoffman, A.R., Ferrell, R.E., Orwoll, E.S. and Zmuda, J.M. (2010) Candidate Gene Analysis of Femoral Neck Trabecular and Cortical Volumetric Bone Mineral Density in Older Men. Journal of Bone and Mineral Research, 25, 330-338. https://doi.org/10.1359/jbmr.090729
[12]
Hopwood, B., Tsykin, A., Findlay, D.M. and Fazzalari, N.L. (2009) Gene Expression Profile of the Bone Microenvironment in Human Fragility Fracture Bone. Bone, 44, 87-101. https://doi.org/10.1016/j.bone.2008.08.120
[13]
Bos, J.M., Subramaniam, M., Hawse, J.R., Christiaans, I., Rajamannan, N.M., Maleszewski, J.J., Edwards, W.D., Wilde, A.A.M., Spelsberg, T.C. and Ackerman, M.J. (2012) TGFβ-Inducible Early Gene-1 (TIEG1) Mutations in Hypertrophic Cardiomyopathy. Journal of Cellular Biochemistry, 113, 1896-1903. https://doi.org/10.1002/jcb.24058
[14]
Kammoun, M., Pouletaut, P., Canon, F., Subramaniam, M., Hawse, J.R., Vayssade, M. and Bensamoun, S.F. (2016) Impact of TIEG1 Deletion on the Passive Mechanical Properties of Fast and Slow Twitch Skeletal Muscles in Female Mice. PLoS ONE, 11, e0164566. https://doi.org/10.1371/journal.pone.0164566
[15]
Kammoun, M., Piquereau, J., Nadal-Desbarats, L., Même, S., Beuvin, M., Bonne, G., Veksler, V., Fur, Y.L., Pouletaut, P., Même, W., Szeremeta, F., Constans, J.-M., Bruinsma, E.S., Holte, M.H.N., Najafova, Z., Johnsen, S.A., Subramaniam, M., Hawse, J.R. and Bensamoun, S.F. (2020) Novel Role of Tieg1 in Muscle Metabolism and Mitochondrial Oxidative Capacities. Acta Physiologica, 228, e13394. https://doi.org/10.1111/apha.13394
[16]
Fine, E.J., Ionita, C.C. and Lohr, L. (2002) The History of the Development of the Cerebellar Examination. Seminars in Neurology, 22, 375-384. https://doi.org/10.1055/s-2002-36759
[17]
Gritti, I. (2013) The Cerebellum, the Hypothalamus and Behavior. Natural Science, 5, 832-834. https://doi.org/10.4236/ns.2013.57100
[18]
álvarez-Rodríguez, R., Barzi, M., Berenguer, J. and Pons, S. (2007) Bone Morphogenetic Protein 2 Opposes Shh-Mediated Proliferation in Cerebellar Granule Cells through a TIEG-1-Based Regulation of Nmyc. Journal of Biological Chemistry, 282, 37170-37180. https://doi.org/10.1074/jbc.M705414200
[19]
Dijkmans, T.F., van Hooijdonk, L.W.A., Schouten, T.G., Kamphorst, J.T., Fitzsimons, C.P. and Vreugdenhil, E. (2009) Identification of New Nerve Growth Factor-Responsive Immediate-Early Genes. Brain Research, 1249, 19-33. https://doi.org/10.1016/j.brainres.2008.10.050
[20]
Spittau, B. and Krieglstein, K. (2012) Klf10 and Klf11 as Mediators of TGF-Beta Superfamily Signaling. Cell and Tissue Research, 347, 65-72. https://doi.org/10.1007/s00441-011-1186-6
[21]
Wibrand, K., Messaoudi, E., Håvik, B., Steenslid, V., Løvlie, R., Steen, V.M. and Bramham, C.R. (2006) Identification of Genes Co-Upregulated with Arc during BDNF-Induced Long-Term Potentiation in Adult Rat Dentate Gyrus in Vivo. European Journal of Neuroscience, 23, 1501-1511. https://doi.org/10.1111/j.1460-9568.2006.04687.x
[22]
Subramaniam, M., Gorny, G., Johnsen, S.A., Monroe, D.G., Evans, G.L., Fraser, D.G., Rickard, D.J., Rasmussen, K., van Deursen, J.M.A., Turner, R.T., Oursler, M.J. and Spelsberg, T.C. (2005) TIEG1 Null Mouse-Derived Osteoblasts Are Defective in Mineralization and in Support of Osteoclast Differentiation in Vitro. Molecular and Cellular Biology, 25, 1191-1199. https://doi.org/10.1128/MCB.25.3.1191-1199.2005
[23]
Kammoun, M., Meme, S., Meme, W., Subramaniam, M., Hawse, J.R., Canon, F. and Bensamoun, S.F. (2017) Impact of TIEG1 on the Structural Properties of Fast- and Slow-Twitch Skeletal Muscle. Muscle & Nerve, 55, 410-416. https://doi.org/10.1002/mus.25252
[24]
Gruetter, R., Fusch, C., Martin, E. and Boesch, C. (1993) Determination of Saturation Factors in 31P NMR Spectra of the Developing Human Brain. Magnetic Resonance in Medicine, 29, 7-11. https://doi.org/10.1002/mrm.1910290104
[25]
Tkáč, I., Starčuk, Z., Choi, I.-Y. and Gruetter, R. (1999) In Vivo 1H NMR Spectroscopy of Rat Brain at 1 ms Echo Time. Magnetic Resonance in Medicine, 41, 649-656. https://doi.org/10.1002/(SICI)1522-2594(199904)41:4<649::AID-MRM2>3.0.CO;2-G
[26]
Ratiney, H., Albers, M.J., Rabeson, H. and Kurhanewicz, J. (2010) Semi-Parametric Time-Domain Quantification of HR-MAS Data from Prostate Tissue. NMR in Biomedicine, 23, 1146-1157. https://doi.org/10.1002/nbm.1541
[27]
Wu, H., Southam, A.D., Hines, A. and Viant, M.R. (2008) High-Throughput Tissue Extraction Protocol for NMR- and MS-Based Metabolomics. Analytical Biochemistry, 372, 204-212. https://doi.org/10.1016/j.ab.2007.10.002
[28]
Beauclercq, S., Nadal-Desbarats, L., Hennequet-Antier, C., Collin, A., Tesseraud, S., Bourin, M., Le Bihan-Duval, E. and Berri, C. (2016) Serum and Muscle Metabolomics for the Prediction of Ultimate pH, a Key Factor for Chicken-Meat Quality. Journal of Proteome Research, 15, 1168-1178. https://doi.org/10.1021/acs.jproteome.5b01050
[29]
Xia, J., Sinelnikov, I.V., Han, B. and Wishart, D.S. (2015) MetaboAnalyst 3.0—Making Metabolomics More Meaningful. Nucleic Acids Research, 43, W251-W257. https://doi.org/10.1093/nar/gkv380
[30]
De Sousa, E., Veksler, V., Minajeva, A., Kaasik, A., Mateo, P., Mayoux, E., Hoerter, J., Bigard, X., Serrurier, B. and Ventura-Clapier, R. (1999) Subcellular Creatine Kinase Alterations. Circulation Research, 85, 68-76. https://doi.org/10.1161/01.RES.85.1.68
[31]
Estornell, E., Fato, R., Pallotti, F. and Lenaz, G. (1993) Assay Conditions for the Mitochondrial NADH: Coenzyme Q Oxidoreductase. FEBS Letters, 332, 127-131. https://doi.org/10.1016/0014-5793(93)80498-J
[32]
Martini, C., Ciana, G., Benettoni, A., Katouzian, F., Severini, G.M., Bussani, R. and Bembi, B. (2001) Intractable Fever and Cortical Neuronal Glycogen Storage in Glycogenosis Type 2. Neurology, 57, 906-908. https://doi.org/10.1212/WNL.57.5.906
[33]
Carre-Pierrat, M., Lafoux, A., Tanniou, G., Chambonnier, L., Divet, A., Fougerousse, F., Huchet-Cadiou, C. and Ségalat, L. (2011) Pre-Clinical Study of 21 Approved Drugs in the Mdx Mouse. Neuromuscular Disorders, 21, 313-327. https://doi.org/10.1016/j.nmd.2011.01.005
[34]
Larcher, T., Lafoux, A., Tesson, L., Remy, S., Thepenier, V., François, V., Guiner, C.L., Goubin, H., Dutilleul, M., Guigand, L., Toumaniantz, G., Cian, A.D., Boix, C., Renaud, J.-B., Cherel, Y., Giovannangeli, C., Concordet, J.-P., Anegon, I. and Huchet, C. (2014) Characterization of Dystrophin Deficient Rats: A New Model for Duchenne Muscular Dystrophy. PLoS ONE, 9, e110371. https://doi.org/10.1371/journal.pone.0110371
[35]
Bagga, D., Khushu, S., Modi, S., Kaur, P., Bhattacharya, D., Garg, M. and Singh, N. (2014) Impaired Visual Information Processing in Alcohol-Dependent Subjects: A Proton Magnetic Resonance Spectroscopy Study of the Primary Visual Cortex. Journal of Studies on Alcohol and Drugs, 75, 817-826. https://doi.org/10.15288/jsad.2014.75.817
[36]
Joe, E., Medina, L.D., Ringman, J.M. and O’Neill, J. (2019) 1H MRS Spectroscopy in Preclinical Autosomal Dominant Alzheimer Disease. Brain Imaging and Behavior, 13, 925-932. https://doi.org/10.1007/s11682-018-9913-1
[37]
Singhal, A., Nagarajan, R., Hinkin, C.H., Kumar, R., Sayre, J., Elderkin-Thompson, V., Huda, A., Gupta, R.K., Han, S.-H. and Thomas, M.A. (2010) Two-Dimensional MR Spectroscopy of Minimal Hepatic Encephalopathy and Neuropsychological Correlates in Vivo. Journal of Magnetic Resonance Imaging, 32, 35-43. https://doi.org/10.1002/jmri.22216
[38]
Ross, B., Kreis, R. and Ernst, T. (1992) Clinical Tools for the 90s: Magnetic Resonance Spectroscopy and Metabolite Imaging. European Journal of Radiology, 14, 128-140. https://doi.org/10.1016/0720-048X(92)90226-Y
[39]
Kim, J.K., Lee, K.S., Chang, H.Y., Lee, W.K. and Lee, J.I. (2014) Progression of Diet Induced Nonalcoholic Steatohepatitis Is Accompanied by Increased Expression of Kruppel-Like-Factor 10 in Mice. Journal of Translational Medicine, 12, 186. https://doi.org/10.1186/1479-5876-12-186
[40]
Leclère, P.S., Rousseau, D., Patouraux, S., Guérin, S., Bonnafous, S., Gréchez-Cassiau, A., Ruberto, A.A., Luci, C., Subramaniam, M., Tran, A., Delaunay, F., Gual, P. and Teboul, M. (2020) MCD Diet-Induced Steatohepatitis Generates a Diurnal Rhythm of Associated Biomarkers and Worsens Liver Injury in Klf10 Deficient Mice. Scientific Reports, 10, Article No. 12139. https://doi.org/10.1038/s41598-020-69085-w
[41]
Papadakis, K.A., Krempski, J., Svingen, P., Xiong, Y., Sarmento, O.F., Lomberk, G.A., Urrutia, R.A. and Faubion, W.A. (2015) Krüppel-Like Factor KLF10 Deficiency Predisposes to Colitis through Colonic Macrophage Dysregulation. American Journal of Physiology-Gastrointestinal and Liver Physiology, 309, G900-G909. https://doi.org/10.1038/s41598-020-69085-w
[42]
Ribeiro, A., Bronk, S.F., Roberts, P.J., Urrutia, R. and Gores, G.J. (1999) The Transforming Growth Factor β1-Inducible Transcription Factor, TIEG1, Mediates Apoptosis through Oxidative Stress. Hepatology, 30, 1490-1497. https://doi.org/10.1002/hep.510300620
[43]
Yang, X., Chen, Q., Sun, L., Zhang, H., Yao, L., Cui, X., Gao, Y., Fang, F. and Chang, Y. (2017) KLF10 Transcription Factor Regulates Hepatic Glucose Metabolism in Mice. Diabetologia, 60, 2443-2452. https://doi.org/10.1007/s00125-017-4412-2
[44]
Urenjak, J., Williams, S.R., Gadian, D.G. and Noble, M. (1992) Specific Expression of N-Acetylaspartate in Neurons, Oligodendrocyte-Type-2 Astrocyte Progenitors, and Immature Oligodendrocytes in Vitro. Journal of Neurochemistry, 59, 55-61. https://doi.org/10.1111/j.1471-4159.1992.tb08875.x
[45]
Kammoun, M., Pouletaut, P., Morandat, S., Subramaniam, M., Hawse, J.R. and Bensamoun, S.F. (2021) Krüppel-Like Factor 10 Regulates the Contractile Properties of Skeletal Muscle Fibers in Mice. Muscle & Nerve, 64, 765-769. https://doi.org/10.1002/mus.27412
