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Title: GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunction
Author: Montero, Raquel
Yubero Siles, Dèlia
Villarroya i Terrade, Joan
Henares, Desiree
Jou, Cristina
Rodríguez, María Angeles
Ramos, Federico
Nascimento, Andrés
Ortez,Carlos Ignacio
Campistol Plana, Jaume
Pérez Dueñas, Belén
O'Callaghan, Mar
Pineda Marfà, Mercè
Garcia-Cazorla, Angeles
Oferil, Jaume Colomer
Montoya, Julio
Ruiz-Pesini, Eduardo.
Emperador, Sonia
Meznaric, Marija
Campderros, Laura
Kalko, Susana
Villarroya i Gombau, Francesc
Artuch Iriberri, Rafael
Jimenez-Mallebrera, Cecilia
Keywords: Mitocondris
Issue Date: 11-Feb-2016
Publisher: Public Library of Science (PLoS)
Abstract: 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 lev- els 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 mitochon- drial dysfunction and that its levels correlate in vitro with FGF-21 levels
Note: Reproducció del document publicat a:
It is part of: PLoS One, 2016, vol. 11, num. 2, p. e0155172
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ISSN: 1932-6203
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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