Abstract
Pompe disease is a metabolic myopathy that is caused by glycogen accumulation as a result of deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Previously, we showed that adult muscle stem cells termed satellite cells are present at normal levels in muscle from patients with Pompe disease, but that these are insufficiently activated to repair the severe muscle pathology. Here we characterized the muscle regenerative response during disease progression in a mouse model of Pompe disease and investigated the intrinsic capacity of Gaa−/− satellite cells to regenerate muscle damage. Gaa−/− mice showed progressive muscle pathology from 15 weeks of age as reflected by increased lysosomal size, decreased fiber diameter and reduced muscle wet weight. Only during the first 15 weeks of life but not thereafter, we detected a gradual increase in centrally nucleated fibers and proliferating satellite cells in Gaa−/− muscle, indicating a mild regenerative response. The levels of Pax7-positive satellite cells were increased in Gaa−/− mice at all ages, most likely as result of enhanced satellite cell activation in young Gaa−/− animals. Surprisingly, both young and old Gaa−/− mice regenerated experimentally-induced muscle injury efficiently as judged by rapid satellite cell activation and complete restoration of muscle histology. In response to serial injury, Gaa−/− mice also regenerated muscle efficiently and maintained the satellite cell pool. These findings suggest that, similar to human patients, Gaa−/− mice have insufficient satellite cell activation and muscle regeneration during disease progression. The initial endogenous satellite cell response in Gaa−/− mice may contribute to the delayed onset of muscle wasting compared to human patients. The rapid and efficient regeneration after experimental muscle injury suggest that Gaa−/− satellite cells are functional stem cells, opening avenues for developing muscle regenerative therapies for Pompe disease.
Highlights
Pompe disease is a metabolic myopathy that is caused by deficiency of acid alpha glucosidase (GAA), a lysosomal enzyme responsible for the degradation of glycogen [38]
Characterization of muscle pathology during disease progression in Gaa−/− mice Previous work has shown that Gaa−/− non-inbred mice display hallmarks of Pompe disease, including progressive skeletal muscle wasting and glycogen accumulation
We performed a more in-depth quantitative analysis of the timing of myofiber pathology and muscle wasting in FVB inbred mice (indicated as Gaa−/−(FVB))
Summary
Pompe disease is a metabolic myopathy that is caused by deficiency of acid alpha glucosidase (GAA), a lysosomal enzyme responsible for the degradation of glycogen [38]. Pompe patients develop progressive skeletal muscle weakness due to lysosomal expansion, followed by lysosomal. Skeletal muscle has the capacity to regenerate upon damage. Given the regenerative properties of skeletal muscle a major unresolved question in the field remains why satellite cells are apparently unable to efficiently repair disease-induced muscle damage. Several explanations have been proposed, including exhaustion of the satellite cell pool [39] or intrinsic failure of satellite cells to regenerate muscle [3, 10]. In Duchenne Muscular Dystrophy, both satellite cell depletion/exhaustion and intrinsic failure of satellite cells to regenerate have been proposed [10, 39]. We have analyzed muscle biopsies from patients with Pompe disease [41]. Our study demonstrated a lack of muscle regeneration to the severe damage observed in biopsies from Pompe patients, even in those from severely affected classic infantile patients. Satellite cells were mostly inactive, in agreement with the lack of detectable muscle regeneration
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
