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


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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Publication Info

Farah, Benjamin L, Lauran Madden, Songtao Li, Sierra Nance, Andrew Bird, Nenad Bursac, Paul M Yen, Sarah P Young, et al. (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

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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 studies of striated muscle biology and disease in vitro and 2) regenerative therapies in small and large animal models in vivo. For in vitro studies, micropatterning of extracellular matrix proteins or protein hydrogels and 3D cell culture are used to engineer rodent and human striated muscle tissues that replicate the structure-function relationships present in healthy and diseased muscles. We use these models to separate and systematically study the roles of structural and genetic factors that contribute cardiac and skeletal muscle function and disease at multiple organizational levels, from single cells to tissues. Combining cardiac and skeletal muscle cells with primary or iPSC-derived non-muscle cells (endothelial cells, smooth muscle cells, immune system cells, neurons) allows us to generate more realistic models of healthy and diseased human tissues and utilize them to mechanistically study molecular and cellular processes of tissue injury, vascularization, innervation, electromechanical integration, fibrosis, and functional repair. Currently, in vitro models of Duchenne Muscular Dystrophy, Pompe disease, dyspherlinopathies, and various cardiomyopathies are studied in the lab. For in vivo studies, we employ rodent models of volumetric skeletal muscle loss, cardiotoxin and BaCl2 injury as well as myocardial infarction and transverse aortic constriction to study how cell, tissue engineering, and gene (viral) therapies can lead to safe and efficient tissue repair and regeneration. In large animal (porcine) models of myocardial injury and arrhythmias, we are exploring how human iPSC derived heart tissue patches and application of engineered ion channels can improve cardiac function and prevent heart failure or sudden cardiac death.



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 fellowship in endocrinology at National Institutes of Health, Bethesda, MD. He was formerly Assistant Professor at Harvard Medical School, Chief of the Neuro-endocrinology and Molecular Regulation Section of the Clinical Endocrinology Branch at NIDDK (at the National Institutes of Health, Bethesda, MD), and Associate Professor of Medicine and Pharmacology at Johns Hopkins University School of Medicine. He has served on the editorial boards of Endocrinology, Molecular Endocrinology, and Thyroid. He also is a U.S. board-certified physician in internal medicine and endocrinology. He is listed as a top 2% scientist worldwide by Stanford University and a leading World Expert on thyroid hormone by Expertscape. He has served as an Asia-Oceanic Thyroid Association (AOTA) Council Member and the AOTA delegate to the World Thyroid Foundation and Singapore Representative to the International Iodine Global Network. He was awarded the 2020 Nagataki-Fujifilm Prize for his contributions to basic and clinical thyroid hormone research in Asia by AOTA. At Duke-NUS, he has served as Master of Sheares Medical College since 2010. He also has served as the clinical faculty advisor for the Duke Overseas Volunteer Expedition (DOVE) program in which medical students deliver primary care in neighbouring underdeveloped countries since its inception in 2010.. His laboratory uses molecular biological and genomic approaches to study hormonal regulation of transcription, autophagy, and metabolism as well as searching for ways to improve the diagnosis and treatment of non-alcoholic fatty liver disease (NAFLD).


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 therapies in patients. I also have an interest in neurometabolic disorders such as the creatine deficiency syndromes and sulfite oxidase and molybdenum cofactors. These disorders can be diagnosed using liquid chromatography-tandem mass spectrometric assays that measure biomarkers in urine. Guanidinoacetate methyltransferase deficiency is a disorder that can be detected in the newborn period and is amenable to dietary therapy, and is thus a good candidate for newborn screening.

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