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Article

Targeted Metabolomic Analysis of a Mucopolysaccharidosis IIIB Mouse Model Reveals an Imbalance of Branched-Chain Amino Acid and Fatty Acid Metabolism

1
Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
2
CEINGE—Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy
*
Author to whom correspondence should be addressed.
These authors equally contributed to this work.
Int. J. Mol. Sci. 2020, 21(12), 4211; https://doi.org/10.3390/ijms21124211
Received: 20 May 2020 / Revised: 9 June 2020 / Accepted: 10 June 2020 / Published: 12 June 2020
(This article belongs to the Special Issue Genetic and Metabolic Molecular Research of Lysosomal Storage Disease)
Mucopolysaccharidoses (MPSs) are inherited disorders of the glycosaminoglycan (GAG) metabolism. The defective digestion of GAGs within the intralysosomal compartment of affected patients leads to a broad spectrum of clinical manifestations ranging from cardiovascular disease to neurological impairment. The molecular mechanisms underlying the progression of the disease downstream of the genetic mutation of genes encoding for lysosomal enzymes still remain unclear. Here, we applied a targeted metabolomic approach to a mouse model of PS IIIB, using a platform dedicated to the diagnosis of inherited metabolic disorders, in order to identify amino acid and fatty acid metabolic pathway alterations or the manifestations of other metabolic phenotypes. Our analysis highlighted an increase in the levels of branched-chain amino acids (BCAAs: Val, Ile, and Leu), aromatic amino acids (Tyr and Phe), free carnitine, and acylcarnitines in the liver and heart tissues of MPS IIIB mice as compared to the wild type (WT). Moreover, Ala, Met, Glu, Gly, Arg, Orn, and Cit amino acids were also found upregulated in the liver of MPS IIIB mice. These findings show a specific impairment of the BCAA and fatty acid catabolism in the heart of MPS IIIB mice. In the liver of affected mice, the glucose-alanine cycle and urea cycle resulted in being altered alongside a deregulation of the BCAA metabolism. Thus, our data demonstrate that an accumulation of BCAAs occurs secondary to lysosomal GAG storage, in both the liver and the heart of MPS IIIB mice. Since BCAAs regulate the biogenesis of lysosomes and autophagy mechanisms through mTOR signaling, impacting on lipid metabolism, this condition might contribute to the progression of the MPS IIIB disease. View Full-Text
Keywords: lysosomal storage diseases; mucopolysaccharidosis IIIB; metabolomics; branched-chain amino acids; acylcarnitines; fatty acids lysosomal storage diseases; mucopolysaccharidosis IIIB; metabolomics; branched-chain amino acids; acylcarnitines; fatty acids
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MDPI and ACS Style

De Pasquale, V.; Caterino, M.; Costanzo, M.; Fedele, R.; Ruoppolo, M.; Pavone, L.M. Targeted Metabolomic Analysis of a Mucopolysaccharidosis IIIB Mouse Model Reveals an Imbalance of Branched-Chain Amino Acid and Fatty Acid Metabolism. Int. J. Mol. Sci. 2020, 21, 4211. https://doi.org/10.3390/ijms21124211

AMA Style

De Pasquale V, Caterino M, Costanzo M, Fedele R, Ruoppolo M, Pavone LM. Targeted Metabolomic Analysis of a Mucopolysaccharidosis IIIB Mouse Model Reveals an Imbalance of Branched-Chain Amino Acid and Fatty Acid Metabolism. International Journal of Molecular Sciences. 2020; 21(12):4211. https://doi.org/10.3390/ijms21124211

Chicago/Turabian Style

De Pasquale, Valeria; Caterino, Marianna; Costanzo, Michele; Fedele, Roberta; Ruoppolo, Margherita; Pavone, Luigi M. 2020. "Targeted Metabolomic Analysis of a Mucopolysaccharidosis IIIB Mouse Model Reveals an Imbalance of Branched-Chain Amino Acid and Fatty Acid Metabolism" Int. J. Mol. Sci. 21, no. 12: 4211. https://doi.org/10.3390/ijms21124211

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