Exploring Desmin as a Potential Modifier in Duchenne Muscular Dystrophy-Associated Cardiomyopathy.

AIM: Duchenne muscular dystrophy (DMD), a rare X-linked genetic disorder, is affecting skeletal and cardiac muscles due to the loss of the dystrophin protein. Modifier proteins, whose expression is altered in DMD patients, may influence disease progression. Desmin, a muscle-specific intermediate filament protein, is increased in the skeletal muscle of mdx mice, a murine model of DMD with a mild phenotype. Here, we inquired whether desmin acts as a modifier in DMD-associated cardiomyopathy.

METHODS: Soluble and insoluble desmin levels were quantified in the hearts of two mdx mouse models (B10.mdx and D2.mdx), and GRMD dystrophic dogs. The expression of desmin-regulatory proteins was also assessed in mdx mice. To assess the impact of desmin levels on the phenotype, we generated mdx mice either desmin-deficient (mdx-Des-/-) or with reduced levels of desmin by introducing a heterozygous desmin knock-out allele (mdx-Des+/-). Phenotypic analyses included cardiac function assessment and histological evaluation.

RESULTS: In mdx mice, desmin was elevated in its insoluble, phosphorylated, and presumably filamentous form, while GRMD dogs with a severe DMD-like phenotype showed no such increase. Desmin deficiency in mdx mice led to severely aggravated dystrophic features, including cardiac dysfunction and increased fibrosis. Moreover, partial desmin reduction in mdx-Des+/- mice led to the abrogation of insoluble desmin increase and worsened the mild mdx dystrophic phenotype.

CONCLUSION: Increased filamentous desmin appears to be protective in mdx mouse hearts and may modulate the severity of DMD cardiomyopathy. These findings support a modifier role for desmin and highlight this protein as a potential therapeutic target for DMD.