The Effect of Uridine on the State of Skeletal Muscles and the Functioning of Mitochondria in Duchenne Dystrophy

Duchenne muscular dystrophy is caused by the loss of functional dystrophin that secondarily causes systemic metabolic impairment in skeletal muscles and cardiomyocytes. The nutraceutical approach is considered as a possible complementary therapy for this pathology. In this work, we have studied the effect of pyrimidine nucleoside uridine (30 mg/kg/day for 28 days, i.p.), which plays an important role in cellular metabolism, on the development of DMD in the skeletal muscles of dystrophin deficient mdx mice, as well as its effect on the mitochondrial dysfunction that accompanies this pathology. We found that chronic uridine administration reduced fibrosis in the skeletal muscles of mdx mice, but it had no effect on the intensity of degeneration/regeneration cycles and inflammation, pseudohypetrophy, and muscle strength of the animals. Analysis of TEM micrographs showed that uridine also had no effect on the impaired mitochondrial ultrastructure of mdx mouse skeletal muscle. The administration of uridine was found to lead to an increase in the expression of the Drp1 and Parkin genes, which may indicate an increase in the intensity of organelle fission and the normalization of mitophagy. Uridine had little effect on OXPHOS dysfunction in mdx mouse mitochondria, and moreover, it was suppressed in the mitochondria of wild type animals. At the same time, uridine restored the transport of potassium ions and reduced the production of reactive oxygen species; however, this had no effect on the impaired calcium retention capacity of mdx mouse mitochondria. The obtained results demonstrate that the used dose of uridine only partially prevents mitochondrial dysfunction in skeletal muscles during Duchenne dystrophy, though it mitigates the development of destructive processes in skeletal muscles.

Automated summary

Duchenne muscular dystrophy is a disease caused by the loss of dystrophin, resulting in metabolic impairment and muscle weakness. This study investigated the potential therapeutic effects of uridine on the skeletal muscles of mdx mice, a model for Duchenne muscular dystrophy. The results showed that uridine administration reduced fibrosis in the muscles, but had no effect on degeneration/regeneration cycles, inflammation, pseudohypertrophy, or muscle strength. Uridine also had no significant impact on mitochondrial function and OXPHOS dysfunction in mdx mouse muscles. However, it increased the expression of Drp1 and Parkin genes, suggesting a potential improvement in organelle fission and mitophagy. Uridine also restored potassium transport and reduced reactive oxygen species production, but did not affect calcium retention capacity in mdx mouse mitochondria.