Sang-Oh Han1, Rand Pope2, Songtao Li1, Priya S Kishnani1, Richard Steet2, Dwight D Koeberl1. 1. Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States. 2. Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA, United States.
Abstract
UNLABELLED: Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) fails to completely reverse muscle weakness in Pompe disease. β2-agonists enhanced ERT by increasing receptor-mediated uptake of rhGAA in skeletal muscles. PURPOSE: To test the hypothesis that a β-blocker might reduce the efficacy of ERT, because the action of β-blockers opposes those of β2-agonists. METHODS: Mice with Pompe disease were treated with propranolol (a β-blocker) or clenbuterol in combination with ERT, or with ERT alone. RESULTS: Propranolol-treated mice had decreased weight gain (p<0.01), in comparison with clenbuterol-treated mice. Left ventricular mass was decreased (and comparable to wild-type) in ERT only and clenbuterol-treated groups of mice, and unchanged in propranolol-treated mice. GAA activity increased following either clenbuterol or propranolol in skeletal muscles. However, muscle glycogen was reduced only in clenbuterol-treated mice, not in propranolol-treated mice. Cell-based experiments confirmed that propranolol reduces uptake of rhGAA into Pompe fibroblasts and also demonstrated that the drug induces intracellular accumulation of glycoproteins at higher doses. CONCLUSION: Propranolol, a commonly prescribed β-blocker, reduced weight, increased left ventricular mass and decreased glycogen clearance in skeletal muscle following ERT. β-Blockers might therefore decrease the efficacy from ERT in patients with Pompe disease.
UNLABELLED: Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) fails to completely reverse muscle weakness in Pompe disease. β2-agonists enhanced ERT by increasing receptor-mediated uptake of rhGAA in skeletal muscles. PURPOSE: To test the hypothesis that a β-blocker might reduce the efficacy of ERT, because the action of β-blockers opposes those of β2-agonists. METHODS:Mice with Pompe disease were treated with propranolol (a β-blocker) or clenbuterol in combination with ERT, or with ERT alone. RESULTS:Propranolol-treated mice had decreased weight gain (p<0.01), in comparison with clenbuterol-treated mice. Left ventricular mass was decreased (and comparable to wild-type) in ERT only and clenbuterol-treated groups of mice, and unchanged in propranolol-treated mice. GAA activity increased following either clenbuterol or propranolol in skeletal muscles. However, muscle glycogen was reduced only in clenbuterol-treated mice, not in propranolol-treated mice. Cell-based experiments confirmed that propranolol reduces uptake of rhGAA into Pompe fibroblasts and also demonstrated that the drug induces intracellular accumulation of glycoproteins at higher doses. CONCLUSION:Propranolol, a commonly prescribed β-blocker, reduced weight, increased left ventricular mass and decreased glycogen clearance in skeletal muscle following ERT. β-Blockers might therefore decrease the efficacy from ERT in patients with Pompe disease.
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