Short term daily deflazacort decreases membrane permeability and increases maximum force in

Duchenne muscular dystrophy (DMD) is a severe genetic disorder caused by the absence of dystrophin, which leads to mechanical instability of the muscle fiber membrane and a predisposition for cell membrane permeability and contraction-induced muscle injury. Deflazacort is an FDA-approved corticosteroid for treating DMD, and treatment of dystrophic mice with deflazacort reduces inflammation and improves muscle regeneration. Whether deflazacort protects from contraction-induced injury in mdx mice is unknown. To address this question, adult mdx mice were administered 1.2 mg/kg deflazacort daily by oral gavage for either 3 or 8-9 weeks and compared to both vehicle-treated mdx mice and wildtype controls for various measures of susceptibility to injury. Both 3 and 8-9 weeks of deflazacort treatment decreased Evans Blue dye (EBD) accumulation in vivo compared to vehicle-treated controls, but the reduction was substantially greater (58% vs. 26%) following shorter-term treatment. Furthermore, for dorsiflexor muscles evaluated in situ, 3 weeks deflazacort treatment dramatically increased isometric force production, and the force decline induced by a single lengthening contraction was reduced more than 50% compared with vehicle-treated controls. Using ex vivo lumbrical muscle preparations, we found that levels of inter-contraction calcium accumulation significantly correlated with force decline during repeated isometric contractions in all deflazacort-treated mice, and a trend for lower aberrant calcium accumulation was seen following 3 weeks of treatment. Given that some protective effects were reduced or not present in a preclinical model of DMD with longer term steroid treatment, these data provide important evidence for beneficial use of short-term deflazacort.