Chemical Chaperone Therapy Reduces Myofiber Damage in Dystrophin‐null mdx Mice

Abstract

Duchenne Muscular Dystrophy (DMD), which affects approximately 1 in 3600 male children, is associated with the absence of the sarcolemmal protein dystrophin, and results in severe muscle weakness, disability and early death. We hypothesize that chronically elevated endoplasmic reticulum (ER) stress is a key player in the pathogenesis of DMD. We therefore predicted that in mdx mice, which model DMD, pharmacotherapy with the chemical chaperone 4‐Phenylbutyric acid (4PBA), which is known to reduce ER stress, will also reduce exercise‐induced muscle damage that is characteristic of dystrophin‐deficiency. In the unexercised tibialis anterior muscle (TA), we found that the ER stress marker CHOP is elevated ~ 3‐fold in mdx versus control mice. Three days after eccentrically‐biased exercise of the TA (90‐180 ° plantarflexion during maximal fused tetany of dorsiflexors; 20 repetitions), there were 9 ± 2 % desmin‐negative damaged fibers in TAs of mdx mice treated with 4PBA (IP injection, 200 mg/kg/day in 0.15M NaHCO3; once daily for 7 days pre‐exercise, daily thereafter until tissue collection) versus 49 ± 7 % damaged fibers in TAs of mdx mice treated with vehicle (N = 2 mice per group); peak tetanic torque of the TA was 75 ± 3 % and 36 ± 3 % of pre‐exercise levels, respectively, in the 4PBA‐ and vehicle‐treated groups (N = 4 mice per group). Data are reported as Mean ± SEM. Our data suggest that relieving ER stress through chemical chaperone therapy might reduce disease severity in patients with DMD.