Pompe disease is a glycogen storage disease caused by a deficiency in acid α-glucosidase (GAA), a hydrolase necessary for the degradation of lysosomal glycogen. This deficiency in GAA results in muscle and neuronal glycogen accumulation, which causes respiratory insufficiency. Pompe disease mouse models provide a means of assessing respiratory pathology and are important for pre-clinical studies of novel therapies that aim to treat respiratory dysfunction and improve quality of life. This review aims to compile and summarize existing manuscripts that characterize the respiratory phenotype of Pompe mouse models. Manuscripts included in this review were selected utilizing specific search terms and exclusion criteria. Analysis of these findings demonstrate that Pompe disease mouse models have respiratory physiological defects as well as pathologies in the diaphragm, tongue, higher-order respiratory control centers, phrenic and hypoglossal motor nuclei, phrenic and hypoglossal nerves, neuromuscular junctions, and airway smooth muscle. Overall, the culmination of these pathologies contributes to severe respiratory dysfunction, underscoring the importance of characterizing the respiratory phenotype while developing effective therapies for patients.

Pompe disease is a lysosomal storage disease caused by mutations within the GAA gene, which encodes acid α-glucosidase (GAA)—an enzyme necessary for lysosomal glycogen degradation. A lack of GAA results in an accumulation of glycogen in cardiac and skeletal muscle, as well as in motor neurons. The only FDA approved treatment for Pompe disease—an enzyme replacement therapy (ERT)—increases survival of patients, but has unmasked previously unrecognized clinical manifestations of Pompe disease. These clinical signs and symptoms include tracheo-bronchomalacia, vascular aneurysms, and gastro-intestinal discomfort. Together, these previously unrecognized pathologies indicate that GAA-deficiency impacts smooth muscle in addition to skeletal and cardiac muscle. Thus, we sought to characterize smooth muscle pathology in the airway, vascular, gastrointestinal, and genitourinary in the Gaa −/− mouse model. Increased levels of glycogen were present in smooth muscle cells of the aorta, trachea, esophagus, stomach, and bladder of Gaa −/− mice, compared to wild type mice. In addition, there was an increased abundance of both lysosome membrane protein (LAMP1) and autophagosome membrane protein (LC3) indicating vacuolar accumulation in several tissues. Taken together, we show that GAA deficiency results in subsequent pathology in smooth muscle cells, which may lead to life-threatening complications if not properly treated.

Pompe disease is a glycogen storage disease caused by a deficiency in acid α-glucosidase (GAA) – a hydrolase necessary for the degradation of lysosomal glycogen. This deficiency in GAA results in muscle and neuronal glycogen accumulation, which causes respiratory insufficiency. Pompe disease rodent models provide a means of assessing respiratory pathology and are important for pre-clinical studies of novel therapies that aim to treat respiratory dysfunction and improve quality of life. This review aims to compile and summarize existing manuscripts which characterize the respiratory phenotype of Pompe rodent models. Manuscripts included in this review were selected utilizing specific search terms and exclusion criteria. Analysis of these findings demonstrate that Pompe disease rodent models have respiratory physiological defects as well as pathologies in the diaphragm, tongue, phrenic and hypoglossal motor nucleus, phrenic and hypoglossal nerves, neuromuscular junctions, and airway smooth muscle and higher order respiratory control centers. Overall, the culmination of these pathologies contributes to severe respiratory dysfunction, underscoring the importance of characterizing the respiratory phenotype while developing effective therapies for patients.

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Duchenne muscular dystrophy (DMD) is the most common X‐linked disease affecting 1 in 3500 male births. DMD is characterized by mutations in the DMD gene, which encodes the protein dystrophin that provides elasticity in skeletal muscle. Mutations in the DMD gene result in a lack of dystrophin which causes muscle fibers to degenerate and leads to inflammation, fibrosis, and muscle atrophy. Boys with DMD have progressive muscle weakness within the diaphragm that leads to respiratory failure in late adolescence/early adulthood. The most common DMD mouse model – the mdx mouse – does not have the same genetic defect as those in humans which makes gene editing impossible in this model. Therefore, a novel mouse model carrying the human gene was created which has the human exon 52 deletion in the dystrophin gene (hDMD/Δ52;mdx). Since respiratory failure is the major cause of morbidity in DMD and needs to be a target for future therapies, we sought to characterize the respiratory pathology in this novel DMD model. Whole body plethysmography (WBP) was used to assess respiration in normoxic air (FiO2: 0.21; nitrogen balance; baseline) and during a challenge with hypercapnic and hypoxic conditions (FiCO2: 0.07, FiO2: 0.10; nitrogen balance). Post mortem studies included immunohistochemistry of the diaphragm and tongue and diaphragm neuromuscular junction analysis. At baseline hDMD/Δ52;mdx mice are indistinguishable from either mdx or wildtype (WT) mice at 2, 6, and 12 months for most measures. However, during the challenge hDMD/Δ52;mdx mice have reduced frequency and minute ventilation by 6 months, which continues to decline at 12 months compared to WT mice. Starting at 6 months of age diaphragm neuromuscular junctions in the hDMD/Δ52;mdx and the mdx mice show similar pathology of decreased colocalization of pre‐ and post‐synaptic endplates. Myofiber atrophy, fibrosis, and regeneration are significant in the diaphragms, but only mild in the tongues of both models. In conclusion, the hDMD/Δ52;mdx exhibits moderate respiratory pathology, and serves as a relevant animal model to study the impact of novel gene editing therapies on respiratory function.