Spatial transcriptomics maps progressive molecular shifts in late-onset Pompe muscle

Researchers have utilized spatial transcriptomics to delineate the progressive molecular changes occurring in the muscle tissue of patients with late-onset Pompe disease. Published in Acta Neuropathologica Communications, the study provides a detailed transcriptomic map that distinguishes between different pathological states of the muscle fibers. The work aims to define specific transcriptional alterations across these distinct fiber states, offering a clearer view of how the disease evolves at the molecular level.

Late-onset Pompe disease is caused by acid alpha-glucosidase deficiency. This deficiency leads to the accumulation of glycogen within lysosomes, resulting in progressive muscle pathology. Traditional muscle biopsies often reveal marked heterogeneity among the fibers, with some appearing non-vacuolated and others displaying vacuoles. The study sought to understand the transcriptomic differences between these two specific fiber populations and healthy control tissue.

To achieve this, the research team performed spatial transcriptomics on muscle sections using the GeoMx Digital Spatial Profiler. The analysis was performed with laminin and LC3B staining. A total of 76 areas of interest were analyzed for the study. This sample included 9 control regions, 35 non-vacuolated Pompe regions, and 32 vacuolated Pompe regions. Genes that were expressed in at least 5% of the regions in at least one condition were retained for further downstream analysis.

The results indicated that even the non-vacuolated Pompe regions showed marked transcriptional alterations when compared with the control regions. These early-stage changes were characterized by the enrichment of pathways related to mitochondrial function and redox homeostasis. Additionally, the non-vacuolated fibers displayed stress-associated pro-apoptotic signalling and MAPK signalling. Structural remodelling was also evident in these regions, suggesting that molecular changes begin before visible vacuolation occurs.

In contrast, the vacuolated Pompe regions displayed a more advanced transcriptional state. These areas showed stronger cytokine-responsive programmes and tissue injury or remodelling signatures. Neuromuscular-associated programmes were also more prominent in the vacuolated fibers. Pathway-level analyses suggested that mitochondrial dysfunction and oxidative stress responses are early features of the disease. As the pathological severity increased, programmes related to the extracellular matrix, fibronectin matrix, and vasculature became more prominent.

The study also highlighted changes associated with muscle regeneration. While regeneration-associated changes were detected across the Pompe muscle, they were most evident in the vacuolated fibers. These regions showed increased central nucleation and co-localization of NCAM1 and LC3B. Patient-level principal component analysis further identified a severity-associated transcriptomic continuum, linking the molecular changes to the progression of the disease.

The findings suggest that late-onset Pompe disease muscle follows a progressive molecular remodelling trajectory across different disease states. Early disease is marked by stress-associated transcriptional remodelling, which includes mitochondrial and apoptotic pathways. As the disease advances, the molecular profile shifts toward increasingly prominent extracellular, inflammatory, regenerative, and structural remodelling programmes.

Subject of Research: Spatial transcriptomic analysis of molecular progression in late-onset Pompe disease muscle

Article Title: Spatial transcriptomics reveals early and progressive molecular changes in late-onset Pompe disease muscle

Article References: Monceau, A., Gallardo, E., Hernández-Lain, A., Paradas, C., Rivas, E., Domínguez-González, C., Papadimas, G., Papadopoulos, C., Chrysanthou-Piterou, M., Kostera-Pruszczyk, A., Kierdaszuk, B., Lilleker, J. B., Roberts, M. E., Musumeci, O., Clark, J., Fernández-Simon, E., Toscano, A., & Díaz-Manera, J. (2026). Spatial transcriptomics reveals early and progressive molecular changes in late-onset Pompe disease muscle. Acta Neuropathologica Communications. https://doi.org/10.1186/s40478-026-02424-6

Image Credits: AI Generated

DOI: 10.1186/s40478-026-02424-6

Keywords: Pompe disease, spatial transcriptomics, muscle pathology, lysosomal storage, gene expression, mitochondrial function, tissue remodelling, neurology, Spatial, transcriptomics, reveals, early