scholarly journals Glycogen accumulation in smooth muscle of a Pompe disease mouse model

2021 ◽  
Vol 57 (0) ◽  
pp. 8-18
Author(s):  
Angela L. McCall ◽  
Justin S. Dhindsa ◽  
Aidan M. Bailey ◽  
Logan A. Pucci ◽  
Laura M. Strickland ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Mouse Model ◽  
Pompe Disease ◽  
Glycogen Accumulation

scholarly journals Airway smooth muscle dysfunction in Pompe (Gaa−/−) mice

2017 ◽  
Vol 312 (6) ◽  
pp. L873-L881 ◽  
Author(s):  
Allison M. Keeler ◽  
Donghai Liu ◽  
Marina Zieger ◽  
Lang Xiong ◽  
Jeffrey Salemi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Smooth Muscle ◽  
Calcium Signaling ◽  
Airway Smooth Muscle ◽  
Respiratory Insufficiency ◽  
Pompe Disease ◽  
Enzyme Deficiency ◽  
Glycogen Accumulation ◽  
Airway Pathology ◽  
Trachea And Bronchi

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.

Glycogen accumulation in smooth muscle in the Pompe disease mouse

2021 ◽  
Vol 132 (2) ◽  
pp. S70
Author(s):  
Angela L. McCall ◽  
Justin S. Dhinsda ◽  
Lucy Zheng ◽  
Aidan M. Bailey ◽  
Laura M. Strickland ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pompe Disease ◽  
Glycogen Accumulation

scholarly journals Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 8
Author(s):  
Yu-Shan Cheng ◽  
Shu Yang ◽  
Junjie Hong ◽  
Rong Li ◽  
Jeanette Beers ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Pompe Disease ◽  
Drug Efficacy ◽  
Cns Involvement ◽  
Glycogen Accumulation ◽  
Induced Pluripotent ◽  
Alpha Glucosidase

Pompe disease is a lysosomal storage disorder caused by autosomal recessive mutations in the acid alpha-glucosidase (GAA) gene. Acid alpha-glucosidase deficiency leads to abnormal glycogen accumulation in patient cells. Given the increasing evidence of central nervous system (CNS) involvement in classic infantile Pompe disease, we used neural stem cells, differentiated from patient induced pluripotent stem cells, to model the neuronal phenotype of Pompe disease. These Pompe neural stem cells exhibited disease-related phenotypes including glycogen accumulation, increased lysosomal staining, and secondary lipid buildup. These morphological phenotypes in patient neural stem cells provided a tool for drug efficacy evaluation. Two potential therapeutic agents, hydroxypropyl-β-cyclodextrin and δ-tocopherol, were tested along with recombinant human acid alpha-glucosidase (rhGAA) in this cell-based Pompe model. Treatment with rhGAA reduced LysoTracker staining in Pompe neural stem cells, indicating reduced lysosome size. Additionally, treatment of diseased neural stem cells with the combination of hydroxypropyl-β-cyclodextrin and δ-tocopherol significantly reduced the disease phenotypes. These results demonstrated patient-derived Pompe neural stem cells could be used as a model to study disease pathogenesis, to evaluate drug efficacy, and to screen compounds for drug discovery in the context of correcting CNS defects.

Presence of neuromuscular and pulmonary deficits in a mouse model of Pompe disease

2016 ◽  
Vol 81 ◽  
pp. 349
Author(s):  
Jill Dalton ◽  
Matthew Abernathy ◽  
Jonelle May ◽  
Marci Harter ◽  
Theodore Baird
Keyword(s):  
Mouse Model ◽  
Pompe Disease

scholarly journals Smooth muscle brain‐derived neurotrophic factor contributes to airway hyperreactivity in a mouse model of allergic asthma

2018 ◽  
Vol 33 (2) ◽  
pp. 3024-3034 ◽  
Author(s):  
Rodney D. Britt ◽  
Michael A. Thompson ◽  
Sarah A. Wicher ◽  
Logan J. Manlove ◽  
Anne Roesler ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Mouse Model ◽  
Allergic Asthma ◽  
Neurotrophic Factor ◽  
Brain Derived Neurotrophic Factor ◽  
Airway Hyperreactivity

scholarly journals Smooth muscle glucose metabolism promotes monocyte recruitment and atherosclerosis in a mouse model of metabolic syndrome

JCI Insight ◽  
2018 ◽  
Vol 3 (11) ◽  
Author(s):  
Valerie Z. Wall ◽  
Shelley Barnhart ◽  
Jenny E. Kanter ◽  
Farah Kramer ◽  
Masami Shimizu-Albergine ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Smooth Muscle ◽  
Glucose Metabolism ◽  
Mouse Model ◽  
Monocyte Recruitment

scholarly journals Pressure-induced constriction is inhibited in a mouse model of reduced βENaC

2009 ◽  
Vol 297 (3) ◽  
pp. R723-R728 ◽  
Author(s):  
Lauren G. VanLandingham ◽  
Kimberly P. Gannon ◽  
Heather A. Drummond
Keyword(s):  
Smooth Muscle ◽  
Mouse Model ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Cerebral Arteries ◽  
Muscle Cells ◽  
Normal Pressure ◽  
Quantitative Immunofluorescence ◽  
Mechanosensitive Ion Channel

Recent studies suggest certain epithelial Na+channel (ENaC) proteins may be components of mechanosensitive ion channel complexes in vascular smooth muscle cells that contribute to pressure-induced constriction in middle cerebral arteries (MCA). However, the role of a specific ENaC protein, βENaC, in pressure-induced constriction of MCAs has not been determined. The goal of this study was to determine whether pressure-induced constriction in the MCA is altered in a mouse model with reduced levels of βENaC. Using quantitative immunofluorescence, we found whole cell βENaC labeling in cerebral vascular smooth muscle cells (VSMCs) was suppressed 46% in βENaC homozygous mutant (m/m) mice compared with wild-type littermates (+/+). MCAs from βENaC +/+ and m/m mice were isolated and placed in a vessel chamber for myographic analysis. Arteries from βENaC+/+ mice constricted to stepwise increases in perfusion pressure and developed maximal tone of 10 ± 2% at 90 mmHg ( n = 5). In contrast, MCAs from βENaC m/m mice developed significantly less tone (4 ± 1% at 90 mmHg, n = 5). Vasoconstrictor responses to KCl (4–80 mM) were identical between genotypes and responses to phenylephrine (10−7-10−4M) were marginally altered, suggesting that reduced levels of VSMC βENaC specifically inhibit pressure-induced constriction. Our findings indicate βENaC is required for normal pressure-induced constriction in the MCA and provide further support for the hypothesis that βENaC proteins are components of a mechanosensor in VSMCs.

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