Airway smooth muscle dysfunction in Pompe (Gaa-/-) mice.
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, theGaa-/-mouse, we compared histology, pulmonary mechanics, airway smooth muscle (ASM) function, and calcium signaling betweenGaa-/-and age-matched wild-type (WT) mice. Lysosomal glycogen accumulation was observed in the smooth muscle of both the bronchi and the trachea inGaa-/-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 inGaa-/-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.
Division of Pulmonary Medicine, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts.|Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts.
Allison M
AM
Keeler
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts.
Donghai
D
Liu
Division of Pulmonary Medicine, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts.|Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts.
Marina
M
Zieger
Division of Pulmonary Medicine, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts.|Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts.
Lang
L
Xiong
Division of Pulmonary Medicine, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts.|Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts.
Jeffrey
J
Salemi
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
Karl
K
Bellvé
Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida; and.
Barry J
BJ
Byrne
Center for Respiratory Research and Rehabilitation, Department of Physical Therapy and McKnight Brain Institute, University of Florida, Gainesville, Florida.
David D
DD
Fuller
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts.
Ronghua
R
ZhuGe
Division of Pulmonary Medicine, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts; mai.elmallah@umassmed.edu.|Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts.
Mai K
MK
ElMallah
D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology*; D011189:Potassium Chloride / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000503:physiopathology; D000520:alpha-Glucosidases / Q000378:metabolism*
D016210:Methacholine Chloride; D011189:Potassium Chloride; D006003:Glycogen; D000520:alpha-Glucosidases; D000420:Albuterol
Pompe disease; airway smooth muscle; glycogen storing disease; pulmonary mechanics