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Abstract

Pompe disease is a lysosomal storage disease due to deficit in acid alpha-glucosidase (GAA) that mainly induces severe skeletal muscle impairment. There is currently no treatment able to correct the skeletal muscle impairment at long term. A better understanding of the physiopathological mechanisms implicated is essential for the development of new therapeutic strategies.

The aims of the present work are i) to characterize skeletal muscle physiopathology of Pompe disease using the Gaa^-/- murine model and ii) to evaluate the impact of FoxO3a overexpression on muscle physiopathology by gene transfer of AAV-FoxO3a.

Gaa^-/- mice exhibit a strong glycogen overload and a progressive autophagic flux disruption, leading to a vacuolization of muscle fibers. Even if it is associated with atrophy and fiber splitting, this vacuolization does not lead to muscle fiber degeneration. Satellite cells, which are responsible of fiber regeneration, remain functional but however display a defect of activation. In Gaa^-/- mice receiving AAV-FoxO3a, we demonstrated that FoxO3a overexpression could improve the skeletal muscle impairments, through the prevention of glycogen overload, autophagic build-up and tissue remodeling. Moreover, neuromuscular function is improved by overexpression of FoxO3a.

Altogether, our findings provide new insight into the skeletal muscle pathophysiology. We positioned FoxO3a as a protective key element against the development of skeletal muscle impairment in Pompe disease.

Thesis supervisors: Marie-Anne Colle, Karl Rouger & Eduard Ayuso

Partners: UMR 1089 - INSERM/Nantes University

Financed by Ministère de la Recherche, de l'Enseignement Supérieur et de l'Innovation

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.

2016-2020