title: GDF-15 Is Elevated in Children with Mitochondrial Diseases and Is Induced by Mitochondrial Dysfunction.
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 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.
authors: Clinical Biochemistry Department, Hospital Sant Joan de Déu, Barcelona, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.
authors: Raquel
authors: R
authors: Montero
authors: Clinical Biochemistry Department, Hospital Sant Joan de Déu, Barcelona, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.
authors: Delia
authors: D
authors: Yubero
authors: Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.|Biochemistry and Molecular Biology Department, Biomedical Institute University of Barcelona (IBUB), Center for Biomedical Research on Obesity and Nutrition (CIBEROBN), Madrid, Spain.
authors: Joan
authors: J
authors: Villarroya
authors: Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundacion Sant Joan de Deu, Barcelona, Spain.
authors: Desiree
authors: D
authors: Henares
authors: Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.|Pathology Department, Hospital Sant Joan de Déu, Barcelona, Spain.
authors: Cristina
authors: C
authors: Jou
authors: Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.|Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundacion Sant Joan de Deu, Barcelona, Spain.
authors: Maria Angeles
authors: MA
authors: Rodríguez
authors: Neuropaediatrics Department, Hospital Sant Joan de Déu, Barcelona, Spain.
authors: Federico
authors: F
authors: Ramos
authors: Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.|Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundacion Sant Joan de Deu, Barcelona, Spain.
authors: Andrés
authors: A
authors: Nascimento
authors: Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.|Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundacion Sant Joan de Deu, Barcelona, Spain.
authors: Carlos Ignacio
authors: CI
authors: Ortez
authors: Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.|Neuropaediatrics Department, Hospital Sant Joan de Déu, Barcelona, Spain.
authors: Jaume
authors: J
authors: Campistol
authors: Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.|Neuropaediatrics Department, Hospital Sant Joan de Déu, Barcelona, Spain.
authors: Belen
authors: B
authors: Perez-Dueñas
authors: Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.|Neuropaediatrics Department, Hospital Sant Joan de Déu, Barcelona, Spain.
authors: Mar
authors: M
authors: O'Callaghan
authors: Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.
authors: Mercedes
authors: M
authors: Pineda
authors: Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.|Neuropaediatrics Department, Hospital Sant Joan de Déu, Barcelona, Spain.
authors: Angeles
authors: A
authors: Garcia-Cazorla
authors: Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundacion Sant Joan de Deu, Barcelona, Spain.
authors: Jaume Colomer
authors: JC
authors: Oferil
authors: Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Biochemistry and Molecular Biology Department, University of Zaragoza, Zaragoza, Spain.
authors: Julio
authors: J
authors: Montoya
authors: Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Biochemistry and Molecular Biology Department, University of Zaragoza, Zaragoza, Spain.|Fundación ARAID, Universidad de Zaragoza, Zaragoza, Spain.
authors: Eduardo
authors: E
authors: Ruiz-Pesini
authors: Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Biochemistry and Molecular Biology Department, University of Zaragoza, Zaragoza, Spain.
authors: Sonia
authors: S
authors: Emperador
authors: Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors: Marija
authors: M
authors: Meznaric
authors: Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.|Biochemistry and Molecular Biology Department, Biomedical Institute University of Barcelona (IBUB), Center for Biomedical Research on Obesity and Nutrition (CIBEROBN), Madrid, Spain.
authors: Laura
authors: L
authors: Campderros
authors: Bioinformatics Core Facility, IDIBAPS, Hospital Clinic, Barcelona, Spain.
authors: Susana G
authors: SG
authors: Kalko
authors: Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.|Biochemistry and Molecular Biology Department, Biomedical Institute University of Barcelona (IBUB), Center for Biomedical Research on Obesity and Nutrition (CIBEROBN), Madrid, Spain.
authors: Francesc
authors: F
authors: Villarroya
authors: Clinical Biochemistry Department, Hospital Sant Joan de Déu, Barcelona, Spain.|Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.
authors: Rafael
authors: R
authors: Artuch
authors: Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.|Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.|Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundacion Sant Joan de Deu, Barcelona, Spain.
authors: Cecilia
authors: C
authors: Jimenez-Mallebrera
mesh_terms: D000293:Adolescent; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood*; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D028361:Mitochondrial Diseases / Q000097:blood*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D009468:Neuromuscular Diseases / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D012372:ROC Curve; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D012333:RNA, Messenger; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors