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Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle
- Source :
- Molecular Genetics and Metabolism. 103:107-112
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
Abstract
- Enzyme replacement therapy (ERT) with acid α-glucosidase has become available for Pompe disease; however, the response of skeletal muscle, as opposed to the heart, has been attenuated. The poor response of skeletal muscle has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle compared to heart. To further understand the role of CI-MPR in Pompe disease, muscle-specific CI-MPR conditional knockout (KO) mice were crossed with GAA-KO (Pompe disease) mice. We evaluated the impact of CI-MPR-mediated uptake of GAA by evaluating ERT in CI-MPR-KO/GAA-KO (double KO) mice. The essential role of CI-MPR was emphasized by the lack of efficacy of ERT as demonstrated by markedly reduced biochemical correction of GAA deficiency and of glycogen accumulations in double KO mice, in comparison with the administration of the same therapeutic doses in GAA-KO mice. Clenbuterol, a selective β(2)-agonist, enhanced the CI-MPR expression in skeletal tissue and also increased efficacy from GAA therapy, thereby confirming the key role of CI-MPR with regard to enzyme replacement therapy in Pompe disease. Biochemical correction improved in both muscle and non-muscle tissues, indicating that therapy could be similarly enhanced in other lysosomal storage disorders. In summary, enhanced CI-MPR expression might improve the efficacy of enzyme replacement therapy in Pompe disease through enhancing receptor-mediated uptake of GAA.
- Subjects :
- Male
congenital, hereditary, and neonatal diseases and abnormalities
medicine.medical_specialty
Endocrinology, Diabetes and Metabolism
Motor Activity
Biology
Biochemistry
Receptor, IGF Type 2
Article
Mice
chemistry.chemical_compound
Endocrinology
Internal medicine
Glycogen storage disease type II
Conditional gene knockout
Genetics
medicine
Animals
Clenbuterol
Enzyme Replacement Therapy
Muscle, Skeletal
Receptor
Molecular Biology
Mice, Knockout
Mannose 6-phosphate receptor
Glycogen
Glycogen Storage Disease Type II
nutritional and metabolic diseases
Skeletal muscle
alpha-Glucosidases
Enzyme replacement therapy
Adrenergic beta-Agonists
medicine.disease
Disease Models, Animal
medicine.anatomical_structure
chemistry
Acid alpha-glucosidase
Subjects
Details
- ISSN :
- 10967192
- Volume :
- 103
- Database :
- OpenAIRE
- Journal :
- Molecular Genetics and Metabolism
- Accession number :
- edsair.doi.dedup.....bc308d5270156a75ae1ec1f5e6f5fd4a