AuthorsKeeler, Allison M.
Bellve, Karl D.
Byrne, Barry J.
Fuller, David D.
Elmallah, Mai K.
UMass Chan AffiliationsHorae Gene Therapy Center
Program in Molecular Medicine
Department of Microbiology and Physiological Systems
Department of Pediatrics, Division of Pediatric Pulmonology
Document TypeJournal Article
KeywordsCellular and Molecular Physiology
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Nervous System Diseases
Nutritional and Metabolic Diseases
MetadataShow full item record
AbstractPompe disease is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase (GAA) - an enzyme responsible for hydrolyzing lysosomal glycogen. Deficiency of GAA leads to systemic glycogen accumulation in the lysosomes of skeletal muscle, motor neurons and smooth muscle. Skeletal muscle and motor neuron pathology are known to contribute to respiratory insufficiency in Pompe disease, but the role of airway pathology has not been evaluated. Here we propose that GAA enzyme deficiency disrupts the function of the trachea and bronchi, and this lower airway pathology contributes to respiratory insufficiency in Pompe disease. Using an established mouse model of Pompe disease - the Gaa-/- mouse - we compared histology, pulmonary mechanics, airway smooth muscle function and calcium signaling between Gaa-/- and age matched wild type (WT) mice. Lysosomal glycogen accumulation was observed in the smooth muscle of both the bronchi and the trachea in Gaa-/- but not WT mice. Furthermore, Gaa-/- mice had hyporesponsive airway resistance and bronchial ring contraction to the bronchoconstrictive agents methacholine (Mch) and potassium chloride (KCl), and to a bronchodilator (albuterol). Finally, calcium signaling during bronchiolar smooth muscle contraction was impaired in Gaa-/- mice indicating impaired extracellular calcium influx. We conclude that GAA enzyme deficiency leads to glycogen accumulation in the trachea and bronchi, and impairs the ability of lower airway smooth muscle to regulate calcium and respond appropriately to bronchodilator or constrictors. Accordingly, airway smooth muscle dysfunction may contribute to respiratory impairments in Pompe disease.
SourceAm J Physiol Lung Cell Mol Physiol. 2017 Jun 1;312(6):L873-L881. doi: 10.1152/ajplung.00568.2016. Epub 2017 Mar 23. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/43563
Related ResourcesLink to Article in PubMed