Background: Duchenne muscle dystrophy (DMD) is one of the most common lethal genetic diseases of children\nworldwide and is 100% fatal. Steroids, the only therapy currently available, are marred by poor efficacy and a high\nside-effect profile. New therapeutic approaches are urgently needed.\nMethods: Here, we leverage PGC-1�±, a powerful transcriptional coactivator known to protect against dystrophy in\nthe mdx murine model of DMD, to search for novel mechanisms of protection against dystrophy.\nResults: We identify heme oxygenase-1 (HO-1) as a potential novel target for the treatment of DMD. Expression of\nHO-1 is blunted in the muscles from the mdx murine model of DMD, and further reduction of HO-1 by genetic\nhaploinsufficiency worsens muscle damage in mdx mice. Conversely, induction of HO-1 pharmacologically protects\nagainst muscle damage. Mechanistically, HO-1 degrades heme into biliverdin, releasing in the process ferrous iron\nand carbon monoxide (CO). We show that exposure to a safe low dose of CO protects against muscle damage in\nmdx mice, as does pharmacological treatment with CO-releasing molecules.\nConclusions: These data identify HO-1 and CO as novel therapeutic agents for the treatment of DMD. Safety\nprofiles and clinical testing of inhaled CO already exist, underscoring the translational potential of these\nobservations.
Loading....