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dc.contributor.authorKeeler, Allison M.
dc.contributor.authorLui, Donghai
dc.contributor.authorZieger, Marina
dc.contributor.authorXiong, Lang
dc.contributor.authorSalemi, Jeffrey
dc.contributor.authorBellve, Karl D.
dc.contributor.authorByrne, Barry J.
dc.contributor.authorFuller, David D.
dc.contributor.authorZhuGe, Ronghua
dc.contributor.authorElmallah, Mai K.
dc.date2022-08-11T08:10:12.000
dc.date.accessioned2022-08-23T16:59:21Z
dc.date.available2022-08-23T16:59:21Z
dc.date.issued2017-06-01
dc.date.submitted2017-06-01
dc.identifier.citationAm J Physiol Lung Cell Mol Physiol. 2017 Jun 1;312(6):L873-L881. doi: 10.1152/ajplung.00568.2016. Epub 2017 Mar 23. <a href="https://doi.org/10.1152/ajplung.00568.2016">Link to article on publisher's site</a>
dc.identifier.issn1040-0605 (Linking)
dc.identifier.doi10.1152/ajplung.00568.2016
dc.identifier.pmid28336814
dc.identifier.urihttp://hdl.handle.net/20.500.14038/43563
dc.description.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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=28336814&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttps://doi.org/10.1152/ajplung.00568.2016
dc.subjectCellular and Molecular Physiology
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectNervous System Diseases
dc.subjectNutritional and Metabolic Diseases
dc.titleAirway smooth muscle dysfunction in Pompe (Gaa-/-) mice
dc.typeArticle
dc.source.journaltitleAmerican journal of physiology. Lung cellular and molecular physiology
dc.source.volume312
dc.source.issue6
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/peds_pp/134
dc.identifier.contextkey10236414
html.description.abstract<p>Pompe 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.</p>
dc.identifier.submissionpathpeds_pp/134
dc.contributor.departmentHorae Gene Therapy Center
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.contributor.departmentDepartment of Pediatrics, Division of Pediatric Pulmonology
dc.source.pagesL873-L881


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