Loss of ribosome specialization in skeletal muscle as a contributing factor for pathophysiology in Duchenne Muscular dystrophy

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy with no effective treatment.

In this project I propose to test a novel hypothesis that the loss of ribosome specialization observed in DMD patients is a primary factor driving the progression of the disease.Skeletal muscle typically express ribosomal protein L3-like (Rpl3-like), instead of the ubiquitously expressed Rpl3.

Preliminary data suggests that RPL3-like-containing ribosomes have acquired a specialized function that is necessary for the maintenance of sarcomeric protein expression.

Data from DMD patients and DMD animal models (mdx mouse & dogs) show a significant downregulation of Rpl3-like expression with a corresponding increase in Rpl3 expression.

In support of my hypothesis, analysis of skeletal muscle from DMD patients revealed that titin and nebulin proteins were barely detectable despite only a modest decrease in their respective mRNA levels.

Given these findings, I will test the hypothesis that the loss of ribosome specialization in DMD causes a gradual decrease in sarcomeric protein expression which contributes to the progression of the disease.Ribosome specialization represents a heretofore unrecognized level of gene regulation.

Thus, this proposal is a radical departure from how the field currently thinks about the underlying cause of the muscle pathology associated with muscular dystrophy and potentially highlights the ribosome as a new therapeutic target for treating DMD.