Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders

Yatsuga, Shuichi; Fujita, Yasunori; Ishii, Akiko; Fukumoto, Yoshihiro; Arahata, Hajime; Kakuma, Tatsuyuki; Kojima, Toshio; Ito, Masafumi; Tanaka, Masashi; Saiki, Reo; Koga, Yasutoshi

doi:10.1002/ana.24506

Cited by 237 publications

(221 citation statements)

References 24 publications

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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%

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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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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).…”

mentioning

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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“…We therefore analyzed its induction in different types of RC dysfunction, and compared the results to those of a newly suggested mitochondrial disease serum biomarker, growth and differentiation factor 15 (GDF15). 6,[16][17][18] We examined S-FGF21 in a variety of nonmitochondrial disorders with some symptoms or signs common to mitochondrial diseases. To deepen understanding of the mechanism of induction, we analyzed samples from 6 genetically modified mouse models with mechanistically different RC defects.…”

Section: Classification Of Evidencementioning

confidence: 99%

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

Lehtonen¹,

Forsström²,

Bottani³

et al. 2016

Neurology

187

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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“…Although mitochondrial diabetes mellitus is common in other muscle-manifested mitochondrial diseases such as MELAS (Yatsuga et al 2012), it has not been evaluated whether diabetes mellitus can affect the serum concentrations of FGF21 and GDF15 in previous studies of these diseases (Liang et al 2014;Yatsuga et al 2015). Moreover, to the best of our knowledge, the level of FGF21 or GDF15 has been rarely evaluated in mitochondrial diabetes mellitus without evident neuromuscular signs.…”

Section: Introductionmentioning

confidence: 96%

“…Recently, serum fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) have been reported to be useful biomarkers for diagnosis and severity assessment of mitochondrial diseases like MELAS (Liang et al 2014;Yatsuga et al 2015). FGF21 is a member of the FGF19 subfamily, which acts in an endocrine fashion to regulate glucose and lipid metabolism (Chavez et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Successful Glycemic Control Decreases the Elevated Serum FGF21 Level without Affecting Normal Serum GDF15 Levels in a Patient with Mitochondrial Diabetes

Murakami

Ueba

Shinoto

et al. 2016

Tohoku J. Exp. Med.

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Mitochondrial diabetes mellitus is a subtype of diabetes linked to mutations in mitochondrial DNA. In patients with mitochondrial diabetes mellitus, the effect of glycemic control on the serum concentrations of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) has not been evaluated. FGF21 and GDF15 have been reported to be useful biomarkers for the diagnosis and severity assessment of mitochondrial diseases like mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Recent studies have shown FGF21 acts in an endocrine fashion to regulate glucose and lipid metabolism in type 2 diabetes mellitus, while the exact biological functions of GDF15 remain unknown. Although mitochondrial diabetes mellitus is commonly found in cases with mitochondrial diseases, the comparison of FGF21 and GDF15 levels between those with and without diabetes has not been performed. Here, we report a 24-year-old woman with mitochondrial diabetes mellitus, who showed a high level of serum FGF21, but not serum GDF15, at diagnosis. In our case, liraglutide, a glucagon-like peptide-1 receptor agonist, added to insulin glargine was effective for her glycemic control and showed no adverse effects, including gastrointestinal symptoms and hypoglycemia, during a 14-week observation. The successful glycemic control caused a decrease in the FGF21 level, without affecting the GDF15 level. Thus, we should consider patients' glycemic control levels in using FGF21 values for the diagnosis of mitochondrial diseases. In addition, sustained GDF15 levels during glycemic treatment in our case suggest the usefulness of GDF15 as a marker for clinical severity of muscle-manifested mitochondrial diseases.

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Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders

Cited by 237 publications

References 24 publications

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

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

Successful Glycemic Control Decreases the Elevated Serum FGF21 Level without Affecting Normal Serum GDF15 Levels in a Patient with Mitochondrial Diabetes

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