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FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia
Irini Manoli, … , Randy J. Chandler, Charles P. Venditti
Irini Manoli, … , Randy J. Chandler, Charles P. Venditti
Published December 6, 2018
Citation Information: JCI Insight. 2018;3(23):e124351. https://doi.org/10.1172/jci.insight.124351.
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Research Article Genetics Metabolism

FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia

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Abstract

Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut–/–;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.

Authors

Irini Manoli, Justin R. Sysol, Madeline W. Epping, Lina Li, Cindy Wang, Jennifer L. Sloan, Alexandra Pass, Jack Gagné, Yiouli P. Ktena, Lingli Li, Niraj S. Trivedi, Bazoumana Ouattara, Patricia M. Zerfas, Victoria Hoffmann, Mones Abu-Asab, Maria G. Tsokos, David E. Kleiner, Caterina Garone, Kristina Cusmano-Ozog, Gregory M. Enns, Hilary J. Vernon, Hans C. Andersson, Stephanie Grunewald, Abdel G. Elkahloun, Christiane L. Girard, Jurgen Schnermann, Salvatore DiMauro, Eva Andres-Mateos, Luk H. Vandenberghe, Randy J. Chandler, Charles P. Venditti

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Figure 1

Phenotypic characterization of the muscle transgenic MMA mouse model.

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Phenotypic characterization of the muscle transgenic MMA mouse model.
(A...
(A) Mut−/−;TgINS-MCK-Mut mice (n = 62 ) exhibit near normal survival compared with the neonatal lethality of Mut–/– mice (n = 42; log-rank Mantel-Cox and Gehan-Breslow-Wilcoxon test, P < 0.0001) and comparable to their heterozygote littermates (n = 46 and 28, respectively; P = NS). (B) Mut-specific activity was undetectable in the liver, kidney, and brain extracts of Mut–/–;TgINS-MCK-Mut mice, while it was approximately 3 times higher in skeletal muscle compared with that in wild-type controls (1.57 ± 0.07 vs. 0.46 ± 0.11nmol/mg protein/min, n = 3, P = 0.001, unpaired t test). (C) [1-13C] propionate in vivo oxidation showed a small but significant increase by the muscle transgene-mediated Mut expression (n = 3, 6, and 4 for Mut+/−, Mut−/−;TgINS-MCK-Mut, and Mut−/−, respectively; P = 0.04 between mice with and without the transgene). (D) Plasma methylmalonic acid concentrations in Mut−/−;TgINS-MCK-Mut mice were lower compared with Mut−/− mice when animals were reared on high-fat and carbohydrate (HFCD) but not on regular chow diet (RD) (P = 0.0006, n = 3–5, 1-way ANOVA with Tukey’s test for multiple comparisons). (E) Somatic growth was impaired, with Mut−/−;TgINS-MCK-Mut mice not exceeding 50% of the weight of their littermates throughout their life span (P = 0.0002). High caloric diet resulted in improved weight compared with regular chow (P = 0.022, n = 7 mice per group). (F) Glomerular filtration rate (GFR) in Mut−/−;TgINS-MCK-Mut mice was 49.15% ± 6.6% of the average GFR in heterozygote mice on HFCD and 32.1 ± 7.89% on RD (n = 3 and 5, P = 0.05 on HFCD and n = 3 and 4, P = 0.035 for RD, Mann-Whitney U test). GFR between the different diets was not significant. Values are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001).

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