Duchenne muscular dystrophy (DMD) is caused by lack of functional
dystrophin and results in progressive myofiber damage and degeneration. In addition, impaired muscle regeneration and
fibrosis contribute to the progressive pathology of DMD. Importantly,
transforming growth factor-β (TGF-β) is implicated in DMD pathology and is known to stimulate
fibrosis and inhibit muscle regeneration. In this study, we present a new strategy to target TGF-β signaling cascades by specifically inhibiting the expression of TGF-β type I receptor
TGFBR1 (ALK5).
Antisense oligonucleotides (AONs) were designed to specifically induce exon skipping of mouse ALK5 transcripts. AON-induced exon skipping of ALK5 resulted in specific downregulation of full-length receptor transcripts in vitro in different cell types, repression of TGF-β activity, and enhanced C2C12 myoblast differentiation. To determine the effect of these AONs in dystrophic muscles, we performed
intramuscular injections of ALK5 AONs in mdx mice, which resulted in a decrease in expression of
fibrosis-related genes and upregulation of Myog expression compared to control AON-injected muscles. In summary, our study presents a novel method to target TGF-β signaling cascades with potential beneficial effects for DMD.