Short-term daily deflazacort decreases membrane permeability and increases maximum force in mdx mice.

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 wk and compared with both vehicle-treated mdx mice and wild-type controls for various measures of susceptibility to injury. Both 3 and 8-9 wk of deflazacort treatment decreased Evans Blue dye (EBD) accumulation in vivo compared with vehicle-treated controls, but the reduction was substantially greater (58% vs. 26%) following shorter-term treatment. Furthermore, for dorsiflexor muscles evaluated in situ, 3 wk 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 intercontraction 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 wk 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 the beneficial use of short-term deflazacort.NEW & NOTEWORTHY Mechanical instability of muscle fiber membranes is a hallmark feature of Duchenne muscular dystrophy (DMD). Glucocorticoids are commonly prescribed in DMD; however, effects on contraction-induced injury and associated mechanisms remain unclear. Here, 3 wk deflazacort in mdx mice substantially reduced Evans Blue dye uptake and the lengthening contraction-induced force decline in vivo and resulted in a strong trend toward blunted calcium uptake during damaging contractions ex vivo. These findings indicate that short-term deflazacort protects from contraction-induced injury.