Adjunctive β2-agonist treatment reduces glycogen independently of receptor-mediated acid α-glucosidase uptake in the limb muscles of mice with Pompe disease.

dc.contributor.author

Farah, Benjamin L

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Madden, Lauran

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Li, Songtao

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Nance, Sierra

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Bird, Andrew

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Bursac, Nenad

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Yen, Paul M

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Young, Sarah P

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Koeberl, Dwight D

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United States

dc.date.accessioned

2015-10-30T14:30:41Z

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2014-05

dc.description.abstract

Enzyme or gene replacement therapy with acid α-glucosidase (GAA) has achieved only partial efficacy in Pompe disease. We evaluated the effect of adjunctive clenbuterol treatment on cation-independent mannose-6-phosphate receptor (CI-MPR)-mediated uptake and intracellular trafficking of GAA during muscle-specific GAA expression with an adeno-associated virus (AAV) vector in GAA-knockout (KO) mice. Clenbuterol, which increases expression of CI-MPR in muscle, was administered with the AAV vector. This combination therapy increased latency during rotarod and wirehang testing at 12 wk, in comparison with vector alone. The mean urinary glucose tetrasaccharide (Glc4), a urinary biomarker, was lower in GAA-KO mice following combination therapy, compared with vector alone. Similarly, glycogen content was lower in cardiac and skeletal muscle following 12 wk of combination therapy in heart, quadriceps, diaphragm, and soleus, compared with vector alone. These data suggested that clenbuterol treatment enhanced trafficking of GAA to lysosomes, given that GAA was expressed within myofibers. The integral role of CI-MPR was demonstrated by the lack of effectiveness from clenbuterol in GAA-KO mice that lacked CI-MPR in muscle, where it failed to reverse the high glycogen content of the heart and diaphragm or impaired wirehang performance. However, the glycogen content of skeletal muscle was reduced by the addition of clenbuterol in the absence of CI-MPR, as was lysosomal vacuolation, which correlated with increased AKT signaling. In summary, β2-agonist treatment enhanced CI-MPR-mediated uptake and trafficking of GAA in mice with Pompe disease, and a similarly enhanced benefit might be expected in other lysosomal storage disorders.

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http://www.ncbi.nlm.nih.gov/pubmed/24448824

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fj.13-244202

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1530-6860

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https://hdl.handle.net/10161/10802

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eng

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Wiley

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FASEB J

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10.1096/fj.13-244202

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acid maltase

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adeno-associated virus

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autophagy

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enzyme replacement therapy

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gene therapy

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mannose-6-phosphate receptor

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Adrenergic beta-2 Receptor Agonists

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Animals

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Cations

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Clenbuterol

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Densitometry

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Dependovirus

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Extremities

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Genetic Vectors

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Glycogen

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Glycogen Storage Disease Type II

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HEK293 Cells

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Humans

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Lysosomes

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Mice

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Mice, Knockout

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Muscle, Skeletal

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Receptor, IGF Type 2

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alpha-Glucosidases

dc.title

Adjunctive β2-agonist treatment reduces glycogen independently of receptor-mediated acid α-glucosidase uptake in the limb muscles of mice with Pompe disease.

dc.type

Journal article

duke.contributor.orcid

Bursac, Nenad|0000-0002-5688-6061

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Young, Sarah P|0000-0002-7671-016X

duke.contributor.orcid

Koeberl, Dwight D|0000-0003-4513-2464

pubs.author-url

http://www.ncbi.nlm.nih.gov/pubmed/24448824

pubs.begin-page

2272

pubs.end-page

2280

pubs.issue

5

pubs.organisational-group

Basic Science Departments

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Biomedical Engineering

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Clinical Science Departments

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Duke

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Duke Cancer Institute

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Institutes and Centers

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Medicine

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Medicine, Cardiology

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Medicine, Endocrinology, Metabolism, and Nutrition

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Molecular Genetics and Microbiology

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Pediatrics

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Pediatrics, Medical Genetics

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Pratt School of Engineering

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School of Medicine

pubs.publication-status

Published

pubs.volume

28

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