Muscle damage begins before visible changes appear in LOPD
Small study's findings highlight value of early therapeutic intervention
Written by |
In late-onset Pompe disease (LOPD), damage to muscles starts before visible changes appear, gradually progressing from stress to inflammation, scarring (fibrosis), and attempts at remodeling and repair, according to a small European study.
“These findings indicate that [disease-associated] remodelling in Pompe muscle begins before [muscle damage becomes] morphologically evident and intensifies as tissue damage advances,” researchers wrote. “This refines the current ultrastructural model of Pompe disease progression and further supports the importance of early therapeutic intervention.”
The study, “Spatial transcriptomics reveals early and progressive molecular changes in late-onset Pompe disease muscle,” was published in Acta Neuropathologica Communications by an international team of researchers.
Researchers looked for early molecular changes in muscle tissue
Pompe disease is a genetic disease that causes muscles to become weaker starting early in infancy (infantile-onset Pompe disease) or later in life (LOPD). It occurs due to a lack of working GAA, an enzyme that breaks down the complex sugar glycogen inside lysosomes, the cell’s recycling centers. Without GAA, glycogen accumulates inside muscle cells and gradually damages them.
Microscopic examination of muscle samples from people living with LOPD “often reveals a mosaic pattern of fibres, with some appearing normal while others showing varying degrees of glycogen accumulation and autophagic vacuoles,” the researchers wrote.
Autophagic vacuoles are structures that cells form to internalize their own damaged structures and proteins and recycle them in lysosomes. In Pompe, autophagic vacuoles typically accumulate due to the inability to fuse with lysosomes.
In this study, the researchers set out to identify early molecular changes in muscle tissue from LOPD patients and how these progress over time.
They used spatial transcriptomics, a technique that measures which genes are active and in which part of the tissue. This allowed them to compare muscle areas with and without visible vacuoles, which are spaces caused partly by accumulated cellular material.
Abnormalities evident in muscle samples without visible vacuoles
The study included muscle samples from 12 adults with LOPD and three adults without Pompe (used as controls). The researchers analyzed 76 tissue areas: nine control areas, 35 areas without visible vacuoles (non-vacuolated areas), and 32 areas with vacuoles. They detected 18,677 genes and selected 5,305 for detailed analysis.
Muscle samples from LOPD patients already showed molecular abnormalities even when they did not have visible vacuoles. Compared with control areas, non-vacuolated areas showed changes in pathways related to mitochondria (the cell’s powerhouses), cellular stress — including programmed cell death — and muscle, nerve cell, and blood vessel remodeling.
Muscle areas without visible vacuoles also showed increased MAPK-responsive signaling. MAPK is a protein that helps cells respond to stress, inflammation, and damage. The p38 branch of MAPK was particularly active, suggesting that those responses begin early in Pompe disease.
As the disease became more severe, cytokines, which are immune signaling proteins, increased. Some genes involved in these changes were particularly active in more severely affected muscle tissue.
The extracellular matrix (ECM) — the network of proteins providing cells with structure — also changed toward remodeling, meaning that damaged muscle was being structurally reorganized.
These changes form a severity-associated [molecular] continuum at the patient level, refining the current model of Pompe muscle progression and highlighting early non-vacuolated disease states as a potential window for therapeutic intervention.
More detailed examination under a microscope showed that muscle samples from LOPD had fibers that varied widely in size. They also had more collagen, an ECM molecule, between fibers. Excess ECM molecules, particularly collagen, are a result of long-term damage and repair that can lead to fibrosis.
Centrally nucleated fibers, which can appear when muscle regenerates after damage, were more common in patients than in controls and tended to be more frequent in vacuolated areas. NCAM1, a marker associated with muscle regeneration, was found together with LC3B, a marker associated with autophagy, the process cells use to remove and recycle damaged material.
Further statistical analyses showed that patients could be arranged along a molecular continuum that broadly followed the severity of disease.
Overall, the study suggests that progressive damage to muscles in Pompe disease begins before visible vacuoles appear.
“Non-vacuolated fibres already exhibit early stress-associated [molecular] changes, whereas vacuolated and more severe regions display more pronounced inflammatory, structural and regenerative signatures,” the researchers wrote. “These changes form a severity-associated [molecular] continuum at the patient level, refining the current model of Pompe muscle progression and highlighting early non-vacuolated disease states as a potential window for therapeutic intervention.”
Leave a comment
Fill in the required fields to post. Your email address will not be published.