Airway smooth muscle dysfunction in Pompe (Gaa-/- ) mice.

Journal Article (Journal Article)

Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-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 (ASM) 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 ASM to regulate calcium and respond appropriately to bronchodilator or constrictors. Accordingly, ASM dysfunction may contribute to respiratory impairments in Pompe disease.

Full Text

Duke Authors

Cited Authors

  • Keeler, AM; Liu, D; Zieger, M; Xiong, L; Salemi, J; Bellvé, K; Byrne, BJ; Fuller, DD; ZhuGe, R; ElMallah, MK

Published Date

  • June 1, 2017

Published In

Volume / Issue

  • 312 / 6

Start / End Page

  • L873 - L881

PubMed ID

  • 28336814

Pubmed Central ID

  • PMC5495946

Electronic International Standard Serial Number (EISSN)

  • 1522-1504

Digital Object Identifier (DOI)

  • 10.1152/ajplung.00568.2016


  • eng

Conference Location

  • United States