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.