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

Abstract

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.

Proteomics Reveals that Methylmalonyl-CoA Mutase Modulates Cell Architecture and Increases Susceptibility to Stress

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Proteomic and Bioinformatic Investigation of Altered Pathways in Neuroglobin-Deficient Breast Cancer Cells

“…A normal distribution of protein intensity from each LC–MS/MS run was assessed. Then, the normal distributions of the data were adjusted using mean-centered scaling and the separation of the experimental groups was validated using PLS-DA by employing MetaboAnalyst 5.0 software [ 46 , 47 ]. After the data preprocessing, the protein fold changes were calculated as the log2 protein difference of the intensity means of the NGB-KO and Neg replicates groups.…”

Sex Affects Human Premature Neonates’ Blood Metabolome According to Gestational Age, Parenteral Nutrition, and Caffeine Treatment

“…All statistical computations were performed with the statistical software STATA version 16 (StatsCorp, College Station, Texas, USA). Multivariate statistical analysis was performed using MetaboAnalyst 4.0 ( ) [ 47 , 48 ]. The dataset was processed to estimate missing values, removing the features with >50% missing values and replacing the remaining ones by using 1/5 of the minimum value of each variable.…”

“…Partial least squares-discriminant analysis (PLS-DA) was used, and the corresponding variable importance on projection (VIP) was estimated for each differentially abundant metabolite [ 47 ].…”