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Satellite cells fail to contribute to muscle repair but are functional in Pompe disease (glycogenosis type II).

ABSTRACT: Pompe disease, which is due to acid alpha-glucosidase deficiency, is characterized by skeletal muscle dysfunction attributed to the accumulation of glycogen-filled lysosomes and autophagic buildup. Despite the extensive tissue damages, 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. Additionally, whether these deficits occur gradually over the disease course is unclear. Using a longitudinal pathophysiological study of two muscles in a Pompe mouse model, here, we report that the enzymatic defect results in a premature saturating glycogen overload and a high number of enlarged lysosomes. The muscles gradually display profound remodeling as the number of autophagic vesicles, centronucleated fibers, and split fibers increases and larger fibers are lost. Only a few regenerated fibers were observed regardless of age, although the SC pool was preserved. Except for the early age, during which higher numbers of activated SCs and myoblasts were observed, no myogenic commitment was observed in response to the damage. Following in vivo injury, we established that muscle retains regenerative potential, demonstrating that the failure of SC participation in repair is related to an activation signal defect. Altogether, our findings provide new insight into the pathophysiology of Pompe disease and highlight that the activation signal defect of SCs compromises muscle repair, which could be related to the abnormal energetic supply following autophagic flux impairment.

SUBMITTER: Lagalice L

PROVIDER: S-EPMC6211565 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Satellite cells fail to contribute to muscle repair but are functional in Pompe disease (glycogenosis type II).

Lagalice Lydie L Pichon Julien J Gougeon Eliot E Soussi Salwa S Deniaud Johan J Ledevin Mireille M Maurier Virginie V Leroux Isabelle I Durand Sylvie S Ciron Carine C Franzoso Francesca F Dubreil Laurence L Larcher Thibaut T Rouger Karl K Colle Marie-Anne MA

Acta neuropathologica communications 20181031 1

Pompe disease, which is due to acid alpha-glucosidase deficiency, is characterized by skeletal muscle dysfunction attributed to the accumulation of glycogen-filled lysosomes and autophagic buildup. Despite the extensive tissue damages, 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. Additionally, whether these deficits occur gradually over the disease course is unclear. Using a l ...[more]

PMID: 30382921

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Project description: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.

Dataset Information

Satellite cells fail to contribute to muscle repair but are functional in Pompe disease (glycogenosis type II).

Publications

Satellite cells fail to contribute to muscle repair but are functional in Pompe disease (glycogenosis type II).

Similar Datasets

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