Accumulation of membrane repair-associated proteins and mature myostatin are novel markers of muscle pathophysiology in Pompe disease
Abstract
Pompe disease is an autosomal recessive metabolic disorder caused by acid alpha-glucosidase deficiency, characterized by progressive skeletal muscle weakness and respiratory insufficiency. Affected muscles exhibit glycogen-filled lysosomes, autophagic build-up, and mitochondrial abnormalities. Despite global myofibrillar disorganization, satellite cells (SCs) fail to activate, due to mechanisms that remain unclear. This study aimed to further characterize the muscle phenotype in Pompe disease, with particular attention to proteins associated with membrane repair processes, as membrane damage is a primary trigger for SC activation. Longitudinal transcriptomic analysis of skeletal muscle from a Pompe disease mouse model, combined with immunohistochemical and biochemical approaches, showed early and sustained overexpression of dysferlin (DYSF), annexin A2 (ANXA2), and AHNAK2. These membrane repair-associated proteins displayed abnormal localization during disease progression, with sarcoplasmic accumulation associated with T-tubules, lysosomes and autophagosomes, respectively. Analysis of muscle biopsies from some patients with late-onset Pompe disease (LOPD) identified similar expression patterns in moderately affected cases, whereas these patterns were less evident or absent in the most severe samples, suggesting stage-dependent redistribution associated with advanced myoarchitectural disorganization. Furthermore, in the mouse model, we observed persistent post-transcriptional accumulation of mature myostatin (MSTN), a key negative regulator of muscle growth, alongside a decrease in the phospho-SMAD3/SMAD3 ratio and reduced SMAD7 expression, which point toward a more complex modulation of its canonical bioactivity rather than a simple increase. Altogether, these findings identify modified distribution proteins linked to membrane repair and dysregulation of MSTN as features of muscle remodeling in Pompe disease.
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BibTeX
@article{babarit2026accumulation,
title = {{Accumulation of membrane repair-associated proteins and mature myostatin are novel markers of muscle pathophysiology in Pompe disease}},
author = {Candice Babarit and Sabrina Jagot and Cindy Schleder and Johan Deniaud and Tiffany Bourgeton and Lydie Lagalice and Lucie Vezzana and Isabelle Leroux and Aurélie Lardenois and Bertrand Evrard and Laurence Dubreil and Jérôme Amiaud and Franck Verrecchia and Chantal Thorin and Alicia Mayeuf-Louchart and Karl Rouger and Marie-Anne Colle and Françoise Bouhour and Marie Csanyi and Jean-Baptiste Davion and Teresinha Evangelista and Pascal Laforêt and Armelle Magot and Pascale Marcorelles and Claude-Alain Maurage and Yann Péréon and Nathalie Streichenberger and Céline Tard},
journal = {Acta Neuropathologica Communications},
year = {2026},
month = jun,
doi = {10.1186/s40478-026-02348-1},
url = {https://hal.inrae.fr/hal-05668679v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Accumulation of membrane repair-associated proteins and mature myostatin are novel markers of muscle pathophysiology in Pompe disease
AU - Candice Babarit
AU - Sabrina Jagot
AU - Cindy Schleder
AU - Johan Deniaud
AU - Tiffany Bourgeton
AU - Lydie Lagalice
AU - Lucie Vezzana
AU - Isabelle Leroux
AU - Aurélie Lardenois
AU - Bertrand Evrard
AU - Laurence Dubreil
AU - Jérôme Amiaud
AU - Franck Verrecchia
AU - Chantal Thorin
AU - Alicia Mayeuf-Louchart
AU - Karl Rouger
AU - Marie-Anne Colle
AU - Françoise Bouhour
AU - Marie Csanyi
AU - Jean-Baptiste Davion
AU - Teresinha Evangelista
AU - Pascal Laforêt
AU - Armelle Magot
AU - Pascale Marcorelles
AU - Claude-Alain Maurage
AU - Yann Péréon
AU - Nathalie Streichenberger
AU - Céline Tard
PY - 2026
DA - 2026/06/23
JO - Acta Neuropathologica Communications
DO - 10.1186/s40478-026-02348-1
UR - https://hal.inrae.fr/hal-05668679v1
AB - Pompe disease is an autosomal recessive metabolic disorder caused by acid alpha-glucosidase deficiency, characterized by progressive skeletal muscle weakness and respiratory insufficiency. Affected muscles exhibit glycogen-filled lysosomes, autophagic build-up, and mitochondrial abnormalities. Despite global myofibrillar disorganization, satellite cells (SCs) fail to activate, due to mechanisms that remain unclear. This study aimed to further characterize the muscle phenotype in Pompe disease, with particular attention to proteins associated with membrane repair processes, as membrane damage is a primary trigger for SC activation. Longitudinal transcriptomic analysis of skeletal muscle from a Pompe disease mouse model, combined with immunohistochemical and biochemical approaches, showed early and sustained overexpression of dysferlin (DYSF), annexin A2 (ANXA2), and AHNAK2. These membrane repair-associated proteins displayed abnormal localization during disease progression, with sarcoplasmic accumulation associated with T-tubules, lysosomes and autophagosomes, respectively. Analysis of muscle biopsies from some patients with late-onset Pompe disease (LOPD) identified similar expression patterns in moderately affected cases, whereas these patterns were less evident or absent in the most severe samples, suggesting stage-dependent redistribution associated with advanced myoarchitectural disorganization. Furthermore, in the mouse model, we observed persistent post-transcriptional accumulation of mature myostatin (MSTN), a key negative regulator of muscle growth, alongside a decrease in the phospho-SMAD3/SMAD3 ratio and reduced SMAD7 expression, which point toward a more complex modulation of its canonical bioactivity rather than a simple increase. Altogether, these findings identify modified distribution proteins linked to membrane repair and dysregulation of MSTN as features of muscle remodeling in Pompe disease.
SN - 2051-5960
ER -