title: Heme oxygenase and carbon monoxide protect from muscle dystrophy.
abstract: Duchenne muscle dystrophy (DMD) is one of the most common lethal genetic diseases of children worldwide and is 100% fatal. Steroids, the only therapy currently available, are marred by poor efficacy and a high side-effect profile. New therapeutic approaches are urgently needed.
  
  
  
  Here, we leverage PGC-1α, a powerful transcriptional coactivator known to protect against dystrophy in the mdx murine model of DMD, to search for novel mechanisms of protection against dystrophy.
  
  
  
  We identify heme oxygenase-1 (HO-1) as a potential novel target for the treatment of DMD. Expression of HO-1 is blunted in the muscles from the mdx murine model of DMD, and further reduction of HO-1 by genetic haploinsufficiency worsens muscle damage in mdx mice. Conversely, induction of HO-1 pharmacologically protects against muscle damage. Mechanistically, HO-1 degrades heme into biliverdin, releasing in the process ferrous iron and carbon monoxide (CO). We show that exposure to a safe low dose of CO protects against muscle damage in mdx mice, as does pharmacological treatment with CO-releasing molecules.
  
  
  
  These data identify HO-1 and CO as novel therapeutic agents for the treatment of DMD. Safety profiles and clinical testing of inhaled CO already exist, underscoring the translational potential of these observations.
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA.|Current address: Cardiovascular Institute, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Mun Chun
authors.initials: MC
authors.lastname: Chan
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA.|Current address: Cardiovascular Institute, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Ziegler
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA.|Current address: Cardiovascular Institute, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Liu
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA.|Present Address: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Rowe
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA.|Current address: Cardiovascular Institute, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Saumya
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.affiliation: Cardiovascular Institute and Institute Diabetes Obesity and Metabolism, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, 11th floor, 3400 Civic Blvd, Philadelphia, 19104, PA, USA. zarany@mail.med.upenn.edu.
authors.forename: Zoltan
authors.identifier: 0000-0003-1368-2453
authors.initials: Z
authors.lastname: Arany
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D002648:Child; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1
keywords: Carbon monoxide; Duchenne muscle dystrophy; HO-1; Heme oxygenase; PGC-1α; mdx