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

Publication ,  Journal Article
Keeler, AM; Liu, D; Zieger, M; Xiong, L; Salemi, J; Bellvé, K; Byrne, BJ; Fuller, DD; ZhuGe, R; ElMallah, MK
Published in: Am J Physiol Lung Cell Mol Physiol
June 1, 2017

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.

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Published In

Am J Physiol Lung Cell Mol Physiol

DOI

EISSN

1522-1504

Publication Date

June 1, 2017

Volume

312

Issue

6

Start / End Page

L873 / L881

Location

United States

Related Subject Headings

  • alpha-Glucosidases
  • Trachea
  • Respiratory System
  • Potassium Chloride
  • Muscle, Skeletal
  • Muscle Contraction
  • Mice
  • Methacholine Chloride
  • Lung
  • Glycogen Storage Disease Type II
 

Citation

APA
Chicago
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MLA
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Keeler, A. M., Liu, D., Zieger, M., Xiong, L., Salemi, J., Bellvé, K., … ElMallah, M. K. (2017). Airway smooth muscle dysfunction in Pompe (Gaa-/- ) mice. Am J Physiol Lung Cell Mol Physiol, 312(6), L873–L881. https://doi.org/10.1152/ajplung.00568.2016
Keeler, Allison M., Donghai Liu, Marina Zieger, Lang Xiong, Jeffrey Salemi, Karl Bellvé, Barry J. Byrne, David D. Fuller, Ronghua ZhuGe, and Mai K. ElMallah. “Airway smooth muscle dysfunction in Pompe (Gaa-/- ) mice.Am J Physiol Lung Cell Mol Physiol 312, no. 6 (June 1, 2017): L873–81. https://doi.org/10.1152/ajplung.00568.2016.
Keeler AM, Liu D, Zieger M, Xiong L, Salemi J, Bellvé K, et al. Airway smooth muscle dysfunction in Pompe (Gaa-/- ) mice. Am J Physiol Lung Cell Mol Physiol. 2017 Jun 1;312(6):L873–81.
Keeler, Allison M., et al. “Airway smooth muscle dysfunction in Pompe (Gaa-/- ) mice.Am J Physiol Lung Cell Mol Physiol, vol. 312, no. 6, June 2017, pp. L873–81. Pubmed, doi:10.1152/ajplung.00568.2016.
Keeler AM, Liu D, Zieger M, Xiong L, Salemi J, Bellvé K, Byrne BJ, Fuller DD, ZhuGe R, ElMallah MK. Airway smooth muscle dysfunction in Pompe (Gaa-/- ) mice. Am J Physiol Lung Cell Mol Physiol. 2017 Jun 1;312(6):L873–L881.

Published In

Am J Physiol Lung Cell Mol Physiol

DOI

EISSN

1522-1504

Publication Date

June 1, 2017

Volume

312

Issue

6

Start / End Page

L873 / L881

Location

United States

Related Subject Headings

  • alpha-Glucosidases
  • Trachea
  • Respiratory System
  • Potassium Chloride
  • Muscle, Skeletal
  • Muscle Contraction
  • Mice
  • Methacholine Chloride
  • Lung
  • Glycogen Storage Disease Type II