Short term estradiol administration improves muscle funcion, decreases CK levels and upregulates p75 neurotrophin receptor in mdx mice

Despite intense efforts, no cure is currently available for Duchenne muscular dystrophy and glucocorticoids are the only drug effective for slowing disease progression. In skeletyal muscle, estrogens have been proven to stimulate growth and regeneration and reduce inflammation and fibrosis. We have used young mdx mice to demonstrate that short-term estradiol administration caused a notable decrease in CK levels and improved motor function. Aiming to decipher the mechanisms of action of estradiol, we analyzed differentially expressed genes in the muscle of mdx mice treated either with estradiol or placebo for 4 weeks, and identified the low-affinity receptor for neurotrophins p75NTR as one of the most upregulated genes. p75NTR protein levels were also increased. No concomitant increase in TrkA and neurotrophins expression was observed. Treatment of mdx mice with a small molecule p75NTR ligand also demonstrated effectiveness in improving muscle function and decreasing CK levels. Remarkably, high levels of p75NTR protein were found in skeletal muscle of patients with DMD. These results suggest that modulation of this pathway could become a novel therapeutic strategy for DMD.