Metabolic Adaptations to Interrupted Glycosaminoglycan Recycling

Abstract

Lysosomal storage diseases (LSD) are metabolic disorders characterized by accumulation of undegraded material. The mucopolysaccharidoses (MPS) are LSDs defined by the storage of glycosaminoglycans. Previously, we hypothesized that cells affected with LSD have increased energy expenditure for biosynthesis because of deficiencies of raw materials sequestered within the lysosome. Thus, LSDs can be characterized as diseases of deficiency as well as overabundance (lysosomal storage). In this study, metabolite analysis identified deficiencies in simple sugars, nucleotides, and lipids in the livers of MPSI mice. In contrast, most amino acids, amino acid derivatives, dipeptides, and urea were elevated. These data suggest that protein catabolism, perhaps because of increased autophagy, is at least partially fulfilling intermediary metabolism. Thus, maintaining glycosaminoglycan synthesis in the absence of recycled precursors results in major shifts in the energy utilization of the cells. A high fat diet increased simple sugars and some fats and lowered the apparent protein catabolism. Interestingly, autophagy, which is increased in several LSDs, is responsive to dietary intervention and is reduced in MPSVII and MPSI mice fed a high fat diet. Although long term dietary treatment improved body weight in MPSVII mice, it failed to improve life span or retinal function. In addition, the ventricular hypertrophy and proximal aorta dilation observed in MPSVII mice were unchanged by a high fat, simple sugar diet. As the mechanism of this energy imbalance is better understood, a more targeted nutrient approach may yet prove beneficial as an adjunct therapy to traditional approaches. Lysosomal storage disease (LSD)2 typically results from a genetic deficiency of an acid hydrolase (1). The material usually degraded by the enzyme now accumulates in the lysosomes of cells throughout the body. In normal cells, some proportion of the degraded material is exported to the cytosol for reuse, thereby reducing the energy burden on the cell (2, 3). In the case of LSDs, more energy must be diverted to the synthesis of raw material because of the impaired recycling. Thus, this class of disorders presents with an energy imbalance caused by a simultaneous excess of stored material and a deficiency of raw material (4).Deficiencies in lysosomal enzymes involved in glycosaminoglycan (GAG) catabolism result in the mucopolysaccharidoses (MPS) (5). The biochemical, histological, and clinical phenotypes of MPS are likely due to a combination of the adaptations to both lysosomal storage and a deficiency of recycled monosaccharides. Maintaining a normal rate of GAG biosynthesis would require newly imported or synthesized monosaccharides, irrespective of the adaptations to stored material. The increased demand for GAG precursors is likely to be considerable. It has been shown previously in cultured cells that reutilization of catabolites from lysosomal GAG degradation is substantial (2). Therefore, the increased energy burden required for de novo synthesis...

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

“…Given the resemblance of the MPS IIIB mouse model to the human disease, 3 we anticipate that the observed profound metabolic impairments in mice in this study also may occur in patients with MPS IIIB. Previous studies also showed broad metabolomic impairments in the liver in mouse models of MPS I and MPS VII, 38 suggesting profound metabolic abnormalities also may occur in different MPS disorders, given that these closely related diseases share many pathological features.…”

Systems biology study of mucopolysaccharidosis using a human metabolic reconstruction network

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