No abstract

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular human disease caused by dystrophin deficiency. The mdx mouse lacks dystrophin protein, yet does not exhibit the debilitating DMD phenotype. Investigating compensatory mechanisms in the mdx mouse may shed new insights into modifying DMD pathogenesis. This study targets two metabolic genes, guanidinoacetate methyltransferase (GAMT) and arginine:glycine amidinotransferase (AGAT) which are required for creatine synthesis. We show that GAMT and AGAT mRNA are up-regulated 5.4- and 1.9-fold respectively in adult mdx muscle compared to C57. In addition, GAMT protein expression is up-regulated at least 2.5-fold in five different muscles of mdx vs. control. Furthermore, we find GAMT immunoreactivity in up to 80% of mature mdx muscle fibers in addition to small regenerating fibers and rare revertants; while GAMT immunoreactivity is equal to background levels in all muscle fibers of mature C57 mice. The up-regulation of the creatine synthetic pathway may help maintain muscle creatine levels and limit cellular energy failure in leaky mdx skeletal muscles. These results may help better understand the mild phenotype of the mdx mouse and may offer new treatment horizons for DMD.

Therapeutic options for Duchenne muscular dystrophy (DMD), the most common and lethal neuromuscular disorder in children, remain elusive. Oxidative damage is implicated as a pertinent factor involved in its pathogenesis. Protandim ® is an over-the-counter supplement with the ability © 2010 by Informa Healthcare USA, Inc. All rights reserved. to induce antioxidant enzymes. In this study we investigated whether Protandim ® provided benefit using surrogate markers and functional measures in the dystrophin-deficient (mdx)mouse model of DMD. Male 3-week-old mdx mice were randomized into two treatment groups: control (receiving standard rodent chow) and Protandim ® -supplemented standard rodent chow. The diets were continued for 6-week and 6-month studies. The endpoints included the oxidative stress marker thiobarbituric acid-reactive substances (TBARS), plasma osteopontin (OPN), plasma paraoxonase (PON1) activity, H&E histology, gadolinium-enhanced magnetic resonance imaging (MRI) of leg muscle and motor functional measurements. The Protandim ® chow diet in mdx mice for 6 months was safe and well tolerated. After 6 months of Protandim ® , a 48% average decrease in plasma TBARS was seen; 0.92 nmol/mg protein in controls versus 0.48 nmol/mg protein in the Protandim ® group (p = .006). At 6 months, plasma OPN was decreased by 57% (p = .001) in the Protandim ® -treated mice. Protandim ® increased the plasma antioxidant enzyme PON1 activity by 35% (p = .018). After 6 months, the mdx mice with Protandim ® showed 38% less MRI signal abnormality (p = .07) than mice on control diet. In this 6-month mdx mouse study, Protandim ® did not significantly alter motor function nor histological criteria.