FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study
Open accessAbstract
Background Muscle biopsy is the gold standard for diagnosis of mitochondrial disorders because of the lack of sensitive biomarkers in serum. Fibroblast growth factor 21 (FGF-21) is a growth factor with regulatory roles in lipid metabolism and the starvation response, and concentrations are raised in skeletal muscle and serum in mice with mitochondrial respiratory chain deficiencies. We investigated in a retrospective diagnostic study whether FGF-21 could be a biomarker for human mitochondrial disorders.Methods We assessed samples from adults and children with mitochondrial disorders or non-mitochondrial neurological disorders (disease controls) from seven study centres in Europe and the USA, and recruited healthy volunteers (healthy controls), matched for age where possible, from the same centres. We used ELISA to measure FGF-21 concentrations in serum or plasma samples (abnormal values were defined as >200 pg/mL). We compared these concentrations with values for lactate, pyruvate, lactate-to-pyruvate ratio, and creatine kinase in serum or plasma and calculated sensitivity, specificity, and positive and negative predictive values for all biomarkers.Findings We analysed serum or plasma from 67 patients (41 adults and 26 children) with mitochondrial disorders, 34 disease controls (22 adults and 12 children), and 74 healthy controls. Mean FGF-21 concentrations in serum were 820 (SD 1151) pg/mL in adult and 1983 (1550) pg/mL in child patients with respiratory chain deficiencies and 76 (58) pg/mL in healthy controls. FGF-21 concentrations were high in patients with mitochondrial disorders affecting skeletal muscle but not in disease controls, including those with dystrophies. In patients with abnormal FGF-21 concentrations in serum, the odds ratio of having a muscle-manifesting mitochondrial disease was 132·0 (95% CI 38·7-450·3). For the identification of muscle-manifesting mitochondrial disease, the sensitivity was 92·3% (95% CI 81·5-97·9%) and specificity was 91·7% (84·8-96·1%). The positive and negative predictive values for FGF-21 were 84·2% (95% CI 72·1-92·5%) and 96·1 (90·4-98·9%). The accuracy of FGF-21 to correctly identify muscle-manifesting respiratory chain disorders was better than that for all conventional biomarkers. The area under the receiver-operating-characteristic curve for FGF-21 was 0·95; by comparison, the values for other biomarkers were 0·83 lactate (p=0·037, 0·83 for pyruvate (p=0·015), 0·72 for the lactate-to-pyruvate ratio (p=0·0002), and 0·77 for creatine kinase (p=0·013).Interpretation Measurement of FGF-21 concentrations in serum identified primary muscle-manifesting respiratory chain deficiencies in adults and children and might be feasible as a first-line diagnostic test for these disorders to reduce the need for muscle biopsy.Funding Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, Molecular Medicine Institute of Finland, University of Helsinki, Helsinki University Central Hospital, Academy of Finland, Novo Nordisk, Arvo and Lea Ylppö Foundation.
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FGF21 can be both a therapeutic agent and a biomarker of disease.
“According to the combination of these variables, FGF21 can be both a therapeutic agent and a biomarker of disease [219].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [219]
FGF21 is a stress-induced myokine proposed as a specific serum biomarker of muscle-specific mitochondrial disorders.
“Moreover, FGF21 is a stress‐induced myokine that has been proposed as a specific serum biomarker of muscle‐specific mitochondrial disorders.17, 20”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [17]
Skeletal muscle is not only a producer but also a target of FGF21 because it expresses the cofactor β-klotho and the FGFRs.
“Recent studies reported that skeletal muscle is not only a producer but also a target of FGF21 because it expresses the cofactor β‐klotho and the FGFRs.6, 13, 14, 17, 18, 19”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [17]
Muscle-dependent systemic release of FGF21 increases with starvation, endoplasmic reticulum stress, mitochondrial dysfunction, obesity, mitochondrial myopathies, and aging.
“In contrast, muscle‐dependent systemic release of FGF21 increases with starvation, endoplasmic reticulum stress, mitochondrial dysfunction, obesity, mitochondrial myopathies, and aging.6, 13, 14, 15, 16, 17, 18, 19”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [17]
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- Authors
- Suomalainen, A., Elo, J. M., Pietiläinen, K. H., Hakonen, A. H., Sevastianova, K., Korpela, M., Isohanni, P., Marjavaara, S. K., Tyni, T., Kiuru-Enari, S., Pihko, H., Darin, N., Õunap, K., Kluijtmans, L. A., Paetau, A., Buzkova, J., Bindoff, L. A., Annunen-Rasila, J., Uusimaa, J., Rissanen, A., Yki-Järvinen, H., Hirano, M., Tulinius, M., Smeitink, J., & Tyynismaa, H.
- Affiliations
- University of Helsinki (FI)
- Helsinki University Hospital (FI)
- Tartu University Hospital (EE)
- Radboud University Medical Center (NL)
- Haukeland University Hospital (NO)
- Oulu University Hospital (FI)
- Columbia University Irving Medical Center (US)
- University of Gothenburg (SE)
- Corresponding author
- Suomalainen, Anu
- ORCID
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 10
- Issue
- 9
- Pages
- 806-818
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC7568343
- OpenAlex
- W2121647203
- Cited by
- 427
- References
- 35
- Citations by year
- 2026: 23 · 2025: 26 · 2024: 30 · 2023: 30 · 2022: 31 · 2021: 30 · 2020: 38 · 2019: 31 · 2018: 36 · 2017: 27 · 2016: 30 · 2015: 21 · 2014: 22 · 2013: 25 · 2012: 15
- FWCI
- 12.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Novo Nordisk
- Sigrid Juséliuksen Säätiö
- Academy of Finland
- Jane ja Aatos Erkon Säätiö
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Keywords
- FGF21, mitochondrial respiratory chain deficiency, mitochondrial disease, biomarkers, serum biomarkers, diagnostic accuracy, skeletal muscle, lactate, pyruvate, creatine kinase, dystrophy, lipid metabolism, starvation response
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Fibroblast Growth Factors, Humans, Infant, Male, Middle Aged, Retrospective Studies, Biomarkers, Muscle, Skeletal, Mitochondrial Diseases, Young Adult
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