title: A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
authors.forename: Sang-Oh
authors.initials: SO
authors.lastname: Han
authors.affiliation: Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA, United States.
authors.forename: Rand
authors.initials: R
authors.lastname: Pope
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
authors.forename: Songtao
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
authors.forename: Priya S
authors.initials: PS
authors.lastname: Kishnani
authors.affiliation: Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, GA, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Steet
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
authors.forename: Dwight D
authors.initials: DD
authors.lastname: Koeberl
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D004336:Drug Antagonism; D004353:Drug Evaluation, Preclinical; D056947:Enzyme Replacement Therapy; D005347:Fibroblasts / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006801:Humans; D018345:Mice, Knockout; D011433:Propranolol / Q000494:pharmacology* / Q000627:therapeutic use; D000520:alpha-Glucosidases / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000319:Adrenergic beta-Antagonists; D006003:Glycogen; D011433:Propranolol; C509951:GAA protein, human; D000520:alpha-Glucosidases
keywords: Acid α-glucosidase (GAA); Enzyme replacement therapy (ERT); Lysosomal storage disorder (LSD); Pompe disease; Propranolol; β-Blocker