FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study

Suomalainen, Anu; Elo, Jenni M.; Pietiläinen, Kirsi H.; Hakonen, Anna H.; Sevastianova, Ksenia; Korpela, Mari Päivikki; Isohanni, Pirjo; Marjavaara, Sanna; Tyni, Tiina; Kiuru-Enari, Sari; Pihko, Helena; Darín, Niklas; Õunap, Katrin; Kluijtmans, Leo A. J.; Paetau, Anders; Buzková, Jana; Bindoff, Laurence A.; Annunen-Rasila, Johanna; Uusimaa, Johanna; Rissanen, Aila; Yki‐Järvinen, Hannele; Hirano, Michio; Tulinius, M.; Smeitink, Jan A.M.; Tyynismaa, Henna

doi:10.1016/s1474-4422(11)70155-7

Cited by 349 publications

(331 citation statements)

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“…Plasma concentration of fibroblast growth factor 21 was borderline elevated to 338 pg/ml (control 250 pg/ml) consistent with mitochondrial impairment. 7 Enzymatic activity of alpha glucosidase in lymphocytes was normal. Molecular analysis of the coding exons of ISCU gene and PDHA1 gene disclosed normal sequence.…”

Section: Clinical Reportmentioning

confidence: 97%

Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy

et al. 2013

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Isolated metabolic myopathies encompass a heterogeneous group of disorders, with mitochondrial myopathies being a subgroup, with depleted skeletal muscle energy production manifesting either by recurrent episodes of myoglobinuria or progressive muscle weakness. In this study, we investigated the genetic cause of a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy. Analysis of enzyme activities of the five respiratory chain complexes in our patients' skeletal muscle showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase. We employed exome sequencing combined with homozygosity mapping to identify a homozygous mutation, c.1A4T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein. The mutation disrupts the ATG initiation translation site resulting in severe reduction of Fdx2 content in the patient muscle and fibroblasts mitochondria. Fdx2 is the second component of the Fe-S cluster biogenesis machinery, the first being IscU that is associated with isolated mitochondrial myopathy. We suggest adding genetic analysis of FDX1L in cases of mitochondrial myopathy especially when associated with reduced activity of the respiratory chain complexes I, II and III.

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Section: Clinical Reportmentioning

confidence: 97%

Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy

et al. 2013

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“…Strikingly, the mRNA levels for myokines associated with mitochondrial myopathy and whole body energy homeostasis, FGF21 and GDF15 (15)(16)(17), are strongly induced in skeletal muscle (Fig. S4 C and D).…”

Section: Induction Of Fgf21 and Gdf15 In Muscle But Not Liver Or Bat mentioning

confidence: 99%

“…In mitochondrial myopathy, muscle mitochondrial stress is associated with the induction of the myokines fibroblast growth factor 21 (FGF21) (15,16) and growth differentiation factor 15 (GDF15) (17). Elevated FGF21 and GDF15 are associated with diabetes and glucose intolerance (18,19) but have been shown to reduce serum glucose and insulin levels (20).…”

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confidence: 99%

Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity

Morrow

Picard

Derbeneva

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Diabetes is associated with impaired glucose metabolism in the presence of excess insulin. Glucose and fatty acids provide reducing equivalents to mitochondria to generate energy, and studies have reported mitochondrial dysfunction in type II diabetes patients. If mitochondrial dysfunction can cause diabetes, then we hypothesized that increased mitochondrial metabolism should render animals resistant to diabetes. This was confirmed in mice in which the heart-muscle-brain adenine nucleotide translocator isoform 1 (ANT1) was inactivated. ANT1-deficient animals are insulin-hypersensitive, glucose-tolerant, and resistant to high fat diet (HFD)-induced toxicity. In ANT1-deficient skeletal muscle, mitochondrial gene expression is induced in association with the hyperproliferation of mitochondria. The ANT1-deficient muscle mitochondria produce excess reactive oxygen species (ROS) and are partially uncoupled. Hence, the muscle respiration under nonphosphorylating conditions is increased. Muscle transcriptome analysis revealed the induction of mitochondrial biogenesis, down-regulation of diabetes-related genes, and increased expression of the genes encoding the myokines FGF21 and GDF15. However, FGF21 was not elevated in serum, and FGF21 and UCP1 mRNAs were not induced in liver or brown adipose tissue (BAT). Hence, increased oxidation of dietary-reducing equivalents by elevated muscle mitochondrial respiration appears to be the mechanism by which ANT1-deficient mice prevent diabetes, demonstrating that the rate of mitochondrial oxidation of calories is important in the etiology of metabolic disease. mitochondria | skeletal muscle | ANT1 | insulin sensitivity

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“…Our original multicenter analysis identified fibroblast growth factor 21 (FGF21) induction in genetically confirmed muscle-manifesting mitochondrial disorders. 2 Serum FGF21 (S-FGF21) was both sensitive and specific for mitochondrial myopathies (MMs), correlating with disease severity and respiratory chain (RC)-deficient muscle fibers, indicating high potential for a serum biomarker for mitochondrial diseases. 2,3 The findings were thereafter replicated in 4 independent cohorts.…”

Section: Classification Of Evidencementioning

confidence: 99%

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

Lehtonen¹,

Forsström²,

Bottani³

et al. 2016

Neurology

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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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FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study

Abstract: 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.

Cited by 349 publications

References 32 publications

Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy

Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy

Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

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