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PLoS One. 2016 Feb 11;11(2):e0148709. doi: 10.1371/journal.pone.0148709. eCollection 2016.

GDF-15 Is Elevated in Children with Mitochondrial Diseases and Is Induced by Mitochondrial Dysfunction.

Author information

1
Clinical Biochemistry Department, Hospital Sant Joan de Déu, Barcelona, Spain.
2
Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, Instituto de Salud Carlos III, Madrid, Spain.
3
Institute of Pediatric Research Sant Joan de Déu, Barcelona, Spain.
4
Biochemistry and Molecular Biology Department, Biomedical Institute University of Barcelona (IBUB), Center for Biomedical Research on Obesity and Nutrition (CIBEROBN), Madrid, Spain.
5
Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Fundacion Sant Joan de Deu, Barcelona, Spain.
6
Pathology Department, Hospital Sant Joan de Déu, Barcelona, Spain.
7
Neuropaediatrics Department, Hospital Sant Joan de Déu, Barcelona, Spain.
8
Biochemistry and Molecular Biology Department, University of Zaragoza, Zaragoza, Spain.
9
Fundación ARAID, Universidad de Zaragoza, Zaragoza, Spain.
10
Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
11
Bioinformatics Core Facility, IDIBAPS, Hospital Clinic, Barcelona, Spain.

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.

PMID:
26867126
PMCID:
PMC4750949
DOI:
10.1371/journal.pone.0148709
[Indexed for MEDLINE]
Free PMC Article

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