48363 20200221144336.0 doi 10.1371/journal.pone.0148709 sideral 94068 ART-2016-94068 eng Montero, R. GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunction 2016 Access copy available to the general public Unrestricted Background: We previously described increased levels of growth and differentiation factor 15 (GDF-15) in skeletal muscle and serum of patients with mitochondrial diseases. Here we evaluated GDF-15 as a biomarker for mitochondrial diseases affecting children and compared it to fibroblast-growth factor 21 (FGF-21). To investigate the mechanism of GDF-15 induction in these pathologies we measured its expression and secretion in response to mitochondrial dysfunction. Methods: We analysed 59 serum samples from 48 children with mitochondrial disease, 19 samples from children with other neuromuscular diseases and 33 samples from aged-matched healthy children. GDF-15 and FGF-21 circulating levels were determined by ELISA. Results: Our results showed that in children with mitochondrial diseases GDF-15 levels were on average increased by 11-fold (mean 4046pg/ml, 1492 SEM) relative to healthy (350, 21) and myopathic (350, 32) controls. The area under the curve for the receiver-operating-characteristic curve for GDF-15 was 0.82 indicating that it has a good discriminatory power. The overall sensitivity and specificity of GDF-15 for a cut-off value of 550pg/mL was 67.8% (54.4%-79.4%) and 92.3%(81.5%-97.9%), respectively. We found that elevated levels of GDF-15 and or FGF-21 correctly identified a larger proportion of patients than elevated levels of GDF-15 or FGF-21 alone. GDF-15, as well as FGF-21, mRNA expression and protein secretion, were significantly induced after treatment of myotubes with oligomycin and that levels of expression of both factors significantly correlated. Conclusions: Our data indicate that GDF-15 is a valuable serum quantitative biomarker for the diagnosis of mitochondrial diseases in children and that measurement of both GDF-15 and FGF-21 improves the disease detection ability of either factor separately. Finally, we demonstrate for the first time that GDF-15 is produced by skeletal muscle cells in response to mitochondrial dysfunction and that its levels correlate in vitro with FGF-21 levels. info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 2.806 2016 MULTIDISCIPLINARY SCIENCES 15 / 63 = 0.238 2016 Q1 T1 1.236 2016 Agricultural and Biological Sciences (miscellaneous) 2016 Q1 Medicine (miscellaneous) 2016 Q1 Biochemistry, Genetics and Molecular Biology (miscellaneous) 2016 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Yubero, D. Villarroya, J. Henares, D. Jou, C. Rodríguez, M.A. Ramos, F. Nascimento, A. Ortez, C.I. Campistol, J. Perez-Dueñas, B. O''Callaghan, M. Pineda, M. Garcia-Cazorla, A. Oferil, J.C. (orcid)0000-0003-1770-6299 Montoya, J. Universidad de Zaragoza (orcid)0000-0002-0269-7337 Ruiz-Pesini, E. Universidad de Zaragoza (orcid)0000-0001-5964-6138 Emperador, S. Meznaric, M. Campderros, L. Kalko, S.G. Villarroya, F. Artuch, R. Jimenez-Mallebrera, C. 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 11, 2 (2016), 0148709 [15 pp] PLoS One PloS one 1932-6203 1069890 http://zaguan.unizar.es/record/48363/files/texto_completo.pdf Versión publicada 101347 http://zaguan.unizar.es/record/48363/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:48363 articulos driver 2020-02-21-13:47:28 ARTICLE