Association of fibroblast growth factor (FGF-21) as a biomarker with primary mitochondrial disorders, but not with secondary mitochondrial disorders (Friedreich Ataxia)

Salehi, Mohammad Hossein; Kamalıdehghan, Behnam; Houshmand, Massoud; Aryani, Omid; Sadeghizadeh, Majid; Mossalaeie, Mir Majid

doi:10.1007/s11033-013-2767-0

Cited by 20 publications

(14 citation statements)

References 29 publications

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“…Although the liver is the main producer of FGF-21 (36), muscle was also described to secrete this endocrine factor, and its production is known to be increased as a consequence of primary but not secondary mitochondrial disorders (37). In this regard, we found circulating FGF-21 levels to be increased, albeit not significantly, in these patients.…”

Section: Acknowledgmentsmentioning

confidence: 48%

BACE-1, PS-1 and sAPPβ Levels Are Increased in Plasma from Sporadic Inclusion Body Myositis Patients: Surrogate Biomarkers among Inflammatory Myopathies

Catalán-García

Garrabou

Morén

et al. 2015

Mol Med

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Sporadic inclusion body myositis (sIBM) is a rare disease that is difficult to diagnose. Muscle biopsy provides three prominent pathological findings: inflammation, mitochondrial abnormalities and fibber degeneration, represented by the accumulation of protein depots constituted by β-amyloid peptide, among others. We aim to perform a screening in plasma of circulating molecules related to the putative etiopathogenesis of sIBM to determine potential surrogate biomarkers for diagnosis. Plasma from 21 sIBM patients and 20 age-and gender-paired healthy controls were collected and stored at -80°C. An additional population of patients with non-sIBM inflammatory myopathies was also included (nine patients with dermatomyositis and five with polymyositis). Circulating levels of inflammatory cytokines ( were assessed with magnetic bead-based assays, real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA) and high-pressure liquid chromatography (HPLC). Despite remarkable trends toward altered plasmatic expression of inflammatory and mitochondrial molecules (increased IL-6, TNF-α, circulating mtDNA and FGF-21 levels and decreased content in CoQ), only amyloidogenic degenerative markers including BACE-1, PS-1 and sAPPβ levels were significantly increased in plasma from sIBM patients compared with controls and other patients with non-sIBM inflammatory myopathies (p < 0.05). Inflammatory, mitochondrial and amyloidogenic degeneration markers are altered in plasma of sIBM patients confirming their etiopathological implication in the disease. Sensitivity and specificity analysis show that BACE-1, PS-1 and sAPPβ represent a good predictive noninvasive tool for the diagnosis of sIBM, especially in distinguishing this disease from polymyositis. Online address: http://www.molmed.org doi: 10.2119/molmed.2015.00168 Marc Catalán-García, Muscle Research and Mitochondrial Function Laboratory, Cellex, IDIBAPS, Faculty of Medicine, University of Barcelona, Department of Internal Medicine-Hospital Clinic of Barcelona, CELLEX 4B, Villarroel 170, 08036 Barcelona, Catalonia, Spain. Phone: +34-93227-5400, Ext. 2907; Fax: +34-93227-9365; E-mail: macatala@clinic.ub.es. Submitted July 8, 2015; Accepted for publication October 27, 2015; Published Online (www.molmed.org) November 3, 2015. Address correspondence to N O V E L P L A S M A T I C B I O M A R K E R S F O R s I B M D I A G N O S I S8 1 8 | C a t a L á n -G a r C í a E t a L . | M O L M E D 2 1 : 8 1 7 -8 2 3 , 2 0 1 5

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Section: Acknowledgmentsmentioning

confidence: 48%

BACE-1, PS-1 and sAPPβ Levels Are Increased in Plasma from Sporadic Inclusion Body Myositis Patients: Surrogate Biomarkers among Inflammatory Myopathies

Catalán-García

Garrabou

Morén

et al. 2015

Mol Med

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“…2,3 The findings were thereafter replicated in 4 independent cohorts. [4][5][6][7] Moderately increased S-FGF21 has also been reported in some nonmitochondrial genetically heterogeneous disease groups, [8][9][10][11][12][13][14][15] leaving the specificity of FGF21 for MM partially open.…”

Section: Classification Of Evidencementioning

confidence: 94%

“…[2][3][4][5][6][7] However, single MM outliers without induction led us to ask whether the mechanism of response was related to specific kinds of dysfunction. Our patient and mouse data, supplemented by literature review, pointed to the highest induction of FGF21 response in disorders that primarily or secondarily affect mitochondrial translation-direct mutations of translation machinery or mtDNA deletions leading to imbalance of mtDNA-encoded tRNAs and rRNAs -but not mutations in structural RC complexes or their assembly factors.…”

Section: Discontinuation Of Statin Treatment and Clinical Remission Omentioning

confidence: 99%

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

Lehtonen¹,

Forsström²,

Bottani³

et al. 2016

Neurology

176

165

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Objective: To validate new mitochondrial myopathy serum biomarkers for diagnostic use. Methods:We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different musclemanifesting mitochondrial dysfunctions.Results: We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p , 0.0001 for both). This is corroborated in mice (mtDNA deletions 1,163 vs 379 pg/mL, p , 0.0001). However, patients and mice with structural respiratory chain subunit or assembly factor defects showed low induction (human 335 pg/mL, p , 0.05; mice 335 pg/mL, not significant). Overall specificities of FGF21 and GDF15 to find patients with mitochondrial myopathy were 89.3% vs 86.4%, and sensitivities 67.3% and 76.0%, respectively. However, GDF15 was increased also in a wide range of nonmitochondrial conditions.Conclusions: S-FGF21 is a specific biomarker for muscle-manifesting defects of mitochondrial translation, including mitochondrial transfer-RNA mutations and primary and secondary mtDNA deletions, the most common causes of mitochondrial disease. However, normal S-FGF21 does not exclude structural respiratory chain complex or assembly factor defects, important to acknowledge in diagnostics. Classification of evidence:This study provides Class III evidence that elevated S-FGF21 accurately distinguishes patients with mitochondrial myopathies from patients with other conditions, and FGF21 and GDF15 mitochondrial myopathy from other myopathies. Neurology ® 2016;87:2290-2299 GLOSSARY ALS 5 amyotrophic lateral sclerosis; CI 5 confidence interval; CK 5 creatine kinase; FGF21 5 fibroblast growth factor 21; GDF15 5 growth and differentiation factor 15; mCRC 5 metastasized colorectal cancer; MM 5 mitochondrial myopathy; mtDNA 5 mitochondrial DNA; PBC 5 primary biliary cirrhosis; PSC 5 primary sclerosing cholangitis; RC 5 respiratory chain; S-FGF21 5 serum FGF21; tRNA 5 transfer RNA.Mitochondrial diseases are the most common form of inherited metabolic disorders. The high variability in clinical manifestation, heterogeneity of genetic causes with .150 known disease genes, 1 and scarcity of sensitive and specific biomarkers make their diagnosis challenging. Our original multicenter analysis identified fibroblast growth factor 21 (FGF21) induction in *These authors contributed equally to this work.

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“…Mitochondrial disease caused by dysfunctional mitochondria is a group of disorders with highly variable phenotypes including mitochondrial myopathy, diabetes mellitus, deafness, optic neuropathy, and multiple sclerosis-type disease. Serum FGF21 levels are significantly increased in human mitochondrial disease and the best predictor of mitochondrial disease among classical indicators including creatine kinase, lactate, and pyruvate ( 65 , 66 ).…”

Section: Serum Endocrine Fgf Levels As Biomarkers For Diseasesmentioning

confidence: 99%

Endocrine FGFs: Evolution, Physiology, Pathophysiology, and Pharmacotherapy

2015

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The human fibroblast growth factor (FGF) family comprises 22 structurally related polypeptides that play crucial roles in neuronal functions, development, and metabolism. FGFs are classified as intracrine, paracrine, and endocrine FGFs based on their action mechanisms. Paracrine and endocrine FGFs are secreted signaling molecules by acting via cell-surface FGF receptors (FGFRs). Paracrine FGFs require heparan sulfate as a cofactor for FGFRs. In contrast, endocrine FGFs, comprising FGF19, FGF21, and FGF23, require α-Klotho or β-Klotho as a cofactor for FGFRs. Endocrine FGFs, which are specific to vertebrates, lost heparan sulfate-binding affinity and acquired a systemic signaling system with α-Klotho or β-Klotho during early vertebrate evolution. The phenotypes of endocrine FGF knockout mice indicate that they play roles in metabolism including bile acid, energy, and phosphate/active vitamin D metabolism. Accumulated evidence for the involvement of endocrine FGFs in human genetic and metabolic diseases also indicates their pathophysiological roles in metabolic diseases, potential risk factors for metabolic diseases, and useful biomarkers for metabolic diseases. The therapeutic utility of endocrine FGFs is currently being developed. These findings provide new insights into the physiological and pathophysiological roles of endocrine FGFs and potential diagnostic and therapeutic strategies for metabolic diseases.

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Association of fibroblast growth factor (FGF-21) as a biomarker with primary mitochondrial disorders, but not with secondary mitochondrial disorders (Friedreich Ataxia)

Cited by 20 publications

References 29 publications

BACE-1, PS-1 and sAPPβ Levels Are Increased in Plasma from Sporadic Inclusion Body Myositis Patients: Surrogate Biomarkers among Inflammatory Myopathies

BACE-1, PS-1 and sAPPβ Levels Are Increased in Plasma from Sporadic Inclusion Body Myositis Patients: Surrogate Biomarkers among Inflammatory Myopathies

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

Endocrine FGFs: Evolution, Physiology, Pathophysiology, and Pharmacotherapy

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