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Abstract

Pompe disease is a lysosomal storage disorder due to acid alpha-glucosidase (GAA) deficiency, resulting in glycogen accumulation in many cell types and particularly in skeletal muscles. Muscle fibers are vacuolized by accumulation of glycogen-filled lysosomes and autophagic buildup that cause structural damages. Despite the extensive tissue damage, a failure of satellite cell (SC) activation and lack of muscle regeneration have been reported in patients. However, the origin of this defective program is unknown.

The aim of the work presented here was to investigate the muscle remodeling and the characteristics of SC in an attempt to better understand the pathogenesis of the disease.

Using a longitudinal histopathological study of two muscles in GAA-KO mice aged from 1.5 to 9 months old, we report that the enzymatic defect results in a premature saturating glycogen overload from the age of 1.5 month. The muscles gradually display profound remodeling as the number of autophagic vesicles, centronucleated fibers, and split fibers increases and larger fibers are lost. Only few regenerated fibers were observed regardless of age, although the SC pool was unchanged. The myogenic capacity of SC was maintained as assessed in vivo following an acute injury and in vitro with the sequential detection of myoblasts, myocytes and myotubes, revealing that SC are functional and that their absence of commitment is related to a defect of activating signal.

Altogether, our findings provide new insight into the pathophysiology of Pompe disease and suggest an energetic origin in order to explain the lack of SC activation observed.

Thesis supervisors: Marie-Anne Colle & Karl Rouger

Financed by Oniris

Associated publications:

• Thesis
• Lagalice L., Pichon J., Gougeon E., Soussi S., Deniaud J., Ledevin M., Maurier V., Leroux I., Durand S., Ciron C., Franzoso F., Dubreil L., Larcher T., Rouger K., Colle M.-A., Satellite cells fail to contribute to muscle repair but are functional in Pompe disease (glycogenosis type II). Acta Neuropathologica Communications, 2018, 6(1):116. DOI: 10.1186/s40478-018-0609-y.

2014-2018