Lifelong glucocorticoid therapy is the standard of care for Duchenne Muscular Dystrophy (DMD). Initially, glucocorticoids (GC) slow DMD muscle deterioration; however, after 2-4yrs, the GC-muscle benefits are lost due to unknown mechanisms. For ethical reasons, clinical studies lack untreated DMD controls; and thus, the GC-impact on DMD muscle and bone disease remains unclear. Towards this end, 3mo mice lacking functional dystrophin (MDX) were treated with 2.1mg/kg/d prednisolone (GC) or placebo. WT mice were given placebos for comparisons to a dystrophin-replete state. Longitudinal in vivo muscle function testing, DXA, and in vivo µCT (N=15) were performed 2 and 4wks after treatment.
Within placebo-mice, MDX exhibited muscle weakness (decreased plantarflexion torque, contraction energy, power), as well as, dysfunctional increases in fatigue and the time needed to contract for all stimulations/timepoints. MDX calf-muscle cross-sectional area was also increased throughout, by in vivo µCT. For bone, MDX BMD (bone mineral density), cancellous bone, and trabecular thickness were decreased by DXA and in vivo µCT. MDX cortical bone was also reduced by ex vivo µCT, and MDX femurs had decreased mechanical properties (structural: stiffness, ultimate load; material: elastic modulus, ultimate stress, toughness) by 3-point-bending.
Within MDX, GC improved muscle function (increased plantarflexion torque, muscle power; decreased fatigue), and blunted DMD-induced calf-muscle area enlargement after 2wks. In contrast, after 4wks, GC no longer improved muscle function (plantarflexion torque, power, fatigue). For bone, GC-induced BMD loss (2wks: 1 vs -4%; 4wks: -2 vs -6%), placebo vs GC. Trabecular bone was thinner after 2wks GC, and cortical bone was decreased and thinner after 4wks GC. GC impaired bone mechanical properties further (decreased stiffness, ultimate load, ultimate stress), indicating GC-induced bone fragility. Overall, these findings are the first to model both the muscle and bone responses to GC, regarding the initial muscle benefits vs further bone loss/fragility observed clinically, in an in vivo DMD musculoskeletal system.