Study IDs amino acid supplement as potential LOPD therapy
Cellular processes altered in patients' muscles, study finds
Several cellular processes, particularly those related to lysosome function and autophagy, are altered in the muscles of people with late-onset Pompe disease (LOPD), and supplementation with an amino acid as a regulator could be a “promising therapeutic approach,” according to a study.
Levels of L-arginine, an amino acid that acts to widen blood vessels, were significantly lower in patients than in healthy controls, indicating that L-arginine supplementation might help, the researchers wrote. Amino acids are the building blocks of proteins, and L-arginine is associated with the regulation of autophagy, a process by which cells break down and reuse old cell parts. Studies have suggested a link between autophagy and Pompe disease.
“Our results provide insights into the pathogenesis [disease processes] of LOPD and suggest potential treatments,” the researchers wrote in the study, “Metabolic and proteomic profiles provide insights on mechanism of late onset Pompe disease,” which was published in Molecular Genetics and Metabolism.
Pompe disease is caused by mutations in the GAA gene that lead to missing or dysfunctional acid alpha-glucosidase (GAA), an enzyme needed to break down glycogen, a complex sugar molecule. Mutations in GAA result in the toxic accumulation of glycogen inside lysosomes, the cellular compartments responsible for the breakdown and recycling of used materials, particularly in muscle cells.
Proteins and metabolites
In LOPD, symptoms appear after the first year of life and typically include progressive muscle weakness and breathing problems. However, “the exact mechanisms resulting in cell and tissue damage and the varying clinical manifestations still require further exploration, especially for LOPD,” the scientists wrote.
They assessed proteins and metabolites (intermediate or end products of metabolism) in the muscle tissue of people with LOPD and healthy controls. For that, they analyzed samples from six LOPD patients and four controls with no differences in age and sex. Patients had a mean age of 22.7 (ages ranged from 15 to 40) and a mean disease course of 9.5 years, and four were male.
A total of 724 proteins were found to be expressed at different levels in people with the disease relative to the controls. Of those, 635 were found at higher levels (upregulated), while 89 were present at lower levels (downregulated).
These changes corresponded with a range of cellular pathways, with those related to lysosome function and autophagy being significantly upregulated. In contrast, proteins related to the cytoskeleton — a structure that helps cells maintain their shape and internal organization — and neurodegeneration were significantly downregulated.
High levels of neurofilament light polypeptide (NEFL), a component of the cytoskeleton that may be released from muscle to blood upon damage, have been shown in the blood of patients with infantile-onset Pompe and to correlate with cognitive function. But the present study found low NEFL levels in the muscles of LOPD patients. “Further studies are needed to explore the association between NEFL and LOPD,” the researchers wrote, though they speculated that these discrepancies may be due to analyzing different types of samples.
As for metabolites, 15 were upregulated and 143 were downregulated in patients.
Among the metabolite-related pathways found to be decreased in patients, the researchers identified the mTOR pathway — a regulator of many cellular functions, including cell growth — and arginine metabolism.
The researchers said a previous study “reported L-arginine deprivation could induce autophagy by inhibiting mTOR pathway,” and “these results indicate that low levels of L-arginine may contribute to the abnormal upregulation of autophagy in LOPD.”
When these data were correlated with analysis of muscle cell damage in LOPD, the researchers found that calmodulin-like protein 3 (CALML3) might be associated with LOPD severity and thus serve as a biomarker.
Overall, the results showed that “supplementation with L-arginine could represent a promising therapeutic approach for LOPD, and CALML3 could serve as a potential biomarker for LOPD severity,” the scientists wrote, though they added that “a study with a larger sample size is needed to confirm the findings of this research.”
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