Adjunctive β2-agonist treatment reduces glycogen independently of receptor-mediated acid α-glucosidase uptake in the limb muscles of mice with Pompe disease.
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.
Type
Journal articleSubject
acid maltaseadeno-associated virus
autophagy
enzyme replacement therapy
gene therapy
mannose-6-phosphate receptor
Adrenergic beta-2 Receptor Agonists
Animals
Cations
Clenbuterol
Densitometry
Dependovirus
Extremities
Genetic Vectors
Glycogen
Glycogen Storage Disease Type II
HEK293 Cells
Humans
Lysosomes
Mice
Mice, Knockout
Muscle, Skeletal
Receptor, IGF Type 2
alpha-Glucosidases
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https://hdl.handle.net/10161/10802Published Version (Please cite this version)
10.1096/fj.13-244202Publication Info
Farah, Benjamin L; Madden, Lauran; Li, Songtao; Nance, Sierra; Bird, Andrew; Bursac,
Nenad; ... Koeberl, Dwight D (2014). Adjunctive β2-agonist treatment reduces glycogen independently of receptor-mediated
acid α-glucosidase uptake in the limb muscles of mice with Pompe disease. FASEB J, 28(5). pp. 2272-2280. 10.1096/fj.13-244202. Retrieved from https://hdl.handle.net/10161/10802.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Nenad Bursac
Professor of Biomedical Engineering
Bursac's research interests include: Stem cell, tissue engineering, and gene based
therapies for heart and muscle regeneration; Cardiac electrophysiology and arrhythmias;
Organ-on-chip and tissue engineering technologies for disease modeling and therapeutic
screening; Small and large animal models of heart and muscle injury, disease, and
regeneration.
The focus of my research is on application of pluripotent stem cells, tissue engineering,
and gene therapy technologies for: 1) basic s
Dwight D. Koeberl
Professor of Pediatrics
As a physician-scientist practicing clinical and biochemical genetics, I am highly
motivated to seek improved therapy for my patients with inherited disorders of metabolism.
The focus of our research has been the development of gene therapy with adeno-associated
virus (AAV) vectors, most recently by genome editing with CRISPR/Cas9. We have developed
gene therapy for inherited disorders of metabolism, especially glycogen storage disease
(GSD) and phenylketonuria (PKU). 1) GSD
Paul Michael Yen
Professor of Medicine
Paul M. Yen currently is Professor at Duke-NUS Graduate Medical School in Singapore
and Head of the Laboratory of Hormonal Regulation in the Cardiovascular and Metabolic
Disorders Program. He also is Professor of Medicine at Duke University School of Medicine,
Durham, NC and a member of the Duke Molecular Physiology Institute. He received his
B.A. in Chemistry from Amherst College and his M.D. from Johns Hopkins. He completed
his residency in internal medicine at University of Chicago and fel
Sarah Phyllis Young
Professor of Pediatrics
As a clinical biochemical geneticist and a director of the Duke Biochemical Genetics
laboratory, my research interests are focused on improving laboratory diagnostics
for rare inherited disorders of metabolism. I am actively involved in the development
of assays using mass spectrometry and other analytical techniques. My current research
on biomarkers for lysosomal storage disorders, such as Fabry and Pompe disease and
the mucopolysaccharidoses includes monitoring the response to novel ther
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