Twice Weekly Steroids and Exercise as Therapy for DMD

This innovative proposal focuses on developing an efficacious therapeutic strategy involving low dose twice weekly glucocorticoid (GC) administration and exercise training for boys affected with Duchenne muscular dystrophy (DMD), a currently incurable disease characterized by rapidly progressive muscle weakness, early loss of ambulation and death. While GC are the only proven treatment to reduce fibrosis and delay loss of ambulation in DMD, chronic daily administration (which is most commonly prescribed) is associated with adverse, often debilitating effects. As an alternate dosing regimen, weekend-only use was shown to retain the benefits and have less impact on weight gain and linear growth, however high doses were used and associated with behavioral issues. Recent work in mice suggests that the same daily dose administered transiently may be effective and have a greater impact on gains in muscle mass, strength and resistance to fatigue compared to daily dosing due to differential effects on gene expression signaling pathways important for muscle remodeling. Exercise, which also induces signaling pathways that lead to remodeling in healthy muscle, may beneficially impact pathophysiology of DMD by recruiting compensatory pathways. Although high intensity or eccentric actions are damaging to dystrophic muscle, a few studies suggest that submaximal exercise is safe and may delay the loss of muscle function in boys with DMD. Despite these exploratory studies suggesting potential, there is a paucity of research on exercise, which reflects our current lack of understanding of specific exercise prescription parameters (type, intensity, target muscle groups) that may be safe and effective for patients with DMD, as well as lack of accessibility to exercise equipment that appropriately and sufficiently induces adaptation in dystrophic muscle. The objective of this work is to define an efficacious GC regimen with minimal side effects, and understand if exercise training can potentially delay disease progression, reverse secondary effects of disuse, and induce beneficial adaptations in boys with DMD.

AIM 1: To determine the 12-month impact of a low dose (0.75 mg/kg x 2 days of prednisone) regimen on weight gain, DMD muscle pathophysiology and physical function. We hypothesize that compared to the standard daily regimen, a twice-weekly regimen will have less impact on body mass index, and equal improvements in the 1-year change in physical function and muscle fat fraction.

AIM 2: To determine impact of a 6-month in-home, moderate intensity, leg exercise training program on muscle pathophysiology and physical function in DMD.