Cell, muscle repair proteins linked to Pompe disease progression: Study
Abnormal buildup, location of proteins could help track damage in patients
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The accumulation and abnormal location of proteins involved in repairing cell membranes and muscle may represent biological markers of Pompe disease progression, according to a study.
Specifically, changes in the molecular repair pathways may help prevent the activation of satellite cells (SCs). SCs typically drive muscle growth and regeneration.
“These data provide new insights into the involvement of membrane repair-associated proteins and regulation of SC activation in Pompe disease,” researchers wrote. Future work will need to more closely assess the relationship between the proteins and satellite cells and determine the significance in humans with Pompe.
The study, “Accumulation of membrane repair-associated proteins and mature myostatin are novel markers of muscle pathophysiology in Pompe disease,” was published in Acta Neuropathologica Communications.
Tissue repair process impaired in Pompe disease
Mutations in the GAA gene cause Pompe disease by disrupting the breakdown of glycogen, a complex sugar. Over time, glycogen builds up in lysosomes, the recycling centers of cells, resulting in progressive muscle weakness and other Pompe symptoms.
Normally, muscle cell degeneration triggers the activation of SCs, which coordinate tissue repair. However, in people with Pompe disease, this process is impaired and SCs remain in an inactive state.
“This is particularly perplexing given that SC number and function are preserved, suggesting the presence of specific, yet unidentified, pathophysiological [disease-related] processes that impair muscle repair in Pompe disease,” the team from France wrote.
The scientists aimed to explore a potential link between the cells’ mechanism to repair membranes and their failure to activate SCs in Pompe disease. To do this, they analyzed gene activity and protein levels in muscle tissue from a mouse model of Pompe disease. They repeated these measurements as the mice grew to assess disease progression.
There were several differences between the cells of Pompe animals and control animals. The proteins dysferlin (DYSF), annexin A2 (ANXA2), and AHNAK2 were all present at significantly higher levels in Pompe cells. Their corresponding genes were also more active. These three proteins are known to play a role in repairing cell membranes.
In addition to differences in protein levels, the researchers found differences in protein locations.
“Our findings … provide compelling evidence of accumulation and redistribution of membrane repair-associated proteins in muscle fibers in Pompe disease,” they wrote.
Proteins present at higher levels in cell body of Pompe muscle cells
In healthy animals, DYSF, ANXA2, and AHNAK2 tended to accumulate in cell membranes. In contrast, the proteins were present at higher levels in the sarcoplasm, or cell body, of Pompe disease muscle cells.
Close analysis showed that DYSF in Pompe muscle cells surrounded T-tubules, grooves in the cells that help with signal transmission. ANXA2 tended to be found around lysosomes. AHNAK2 was near autophagosomes, small compartments that pick out cellular waste before it accumulates and causes damage.
To test if these patterns translated to humans, the team analyzed muscle tissue samples from three people with late-onset Pompe, whose disease severity ranged from mild to severe.
Muscle fibers from the person with mild Pompe disease showed the highest levels of DYSF, ANXA2, and AHNAK2 in the cell membranes, as was the case with control animals. In the moderate and severe cases, as with the Pompe disease animals, the proteins were more prominent in the sarcoplasm.
“This abnormal sarcoplasmic build-up of these different proteins is an early-onset phenomenon that progresses to advanced stages of the disease … making these proteins potentially valuable markers of Pompe disease progression,” the researchers wrote.
Moderate Pompe disease cells showed DYSF, ANXA2, and AHNAK2 around T-tubules, lysosomes, and autophagosomes, respectively, mimicking the animal model.
This abnormal sarcoplasmic build-up of these different proteins is an early-onset phenomenon that progresses to advanced stages of the disease … making these proteins potentially valuable markers of Pompe disease progression.
However, these patterns didn’t hold for the person with severe Pompe disease, suggesting that membrane repair pathways may continue to evolve as the disease progresses.
In addition to proteins involved in membrane repair, the team also examined myostatin, a protein that inhibits muscle repair by preventing SC activation.
In Pompe disease mice, the gene that contains the blueprint for myostatin (MSTN) was less active than in healthy mice. However, protein levels of MSTN were higher in the Pompe animals than in the control animals.
“This observation shows an increasing divergence in protein [production] as the disease progresses,” the investigators wrote.
High MSTN could potentially help explain why SCs don’t activate to repair muscles in people with Pompe disease, according to the team.
“Within this framework, we can hypothesize that [myostatin] dysregulation may contribute to the lack of SC activation observed in Pompe disease,” the scientists wrote.
Future studies using mice and a larger number of patients will need to test this relationship further to confirm an association between myostatin and SCs in Pompe disease, and to better understand the interactions between DYSF, ANXA2, and AHNAK2, the researchers concluded.
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