Levels of inflammation and oxidative stress, and a role for taurine in dystropathology of the Golden Retriever Muscular Dystrophy dog model for Duchenne Muscular Dystrophy.
Duchenne Muscular Dystrophy (DMD) is a fatal skeletal muscle wasting disease presenting with excessive myofibre necrosis and increased inflammation and oxidative stress. In the mdx mouse model of DMD, homeostasis of the amino acid taurine is altered, and taurine administration drastically decreases muscle necrosis, dystropathology, inflammation and protein thiol oxidation. Since the severe pathology of the Golden Retriever Muscular Dystrophy (GRMD) dog model more closely resembles the human DMD condition, we aimed to assess the generation of oxidants by inflammatory cells and taurine metabolism in this species. In muscles of 8 month GRMD dogs there was an increase in the content of neutrophils and macrophages, and an associated increase in elevated myeloperoxidase, a protein secreted by neutrophils that catalyses production of the highly reactive hypochlorous acid (HOCl). There was also increased chlorination of tyrosines, a marker of HOCl generation, increased thiol oxidation of many proteins and irreversible oxidative protein damage. Taurine, which functions as an antioxidant by trapping HOCl, was reduced in GRMD plasma; however taurine was increased in GRMD muscle tissue, potentially due to increased muscle taurine transport and synthesis. These data indicate a role for HOCl generated by neutrophils in the severe dystropathology of GRMD dogs, which may be exacerbated by decreased availability of taurine in the blood. These novel data support continued research into the precise roles of oxidative stress and taurine in DMD and emphasise the value of the GRMD dogs as a suitable pre-clinical model for testing taurine as a therapeutic intervention for DMD boys.
School of Chemistry and Biochemistry, the University of Western Australia, Perth, Western Australia, Australia; School of Anatomy, Physiology and Human Biology, the University of Western Australia, Perth, Western Australia, Australia. Electronic address: jessica.terrill@uwa.edu.au.
Jessica R
JR
Terrill
School of Chemistry and Biochemistry, the University of Western Australia, Perth, Western Australia, Australia.
Marisa N
MN
Duong
Centre for Free Radical Research, Department of Pathology, the University of Otago, Christchurch, New Zealand.
Rufus
R
Turner
Atlantic Gene Therapies, INSERM UMR1089, Nantes, France; Genethon, Evry, France.
Caroline
C
Le Guiner
School of Chemistry and Biochemistry, the University of Western Australia, Perth, Western Australia, Australia.
Amber
A
Boyatzis
Centre for Free Radical Research, Department of Pathology, the University of Otago, Christchurch, New Zealand.
Anthony J
AJ
Kettle
School of Anatomy, Physiology and Human Biology, the University of Western Australia, Perth, Western Australia, Australia.
Miranda D
MD
Grounds
School of Chemistry and Biochemistry, the University of Western Australia, Perth, Western Australia, Australia.
Peter G
PG
Arthur
D000818:Animals; D015415:Biomarkers; D004195:Disease Models, Animal; D004285:Dogs; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D015415:Biomarkers; D009124:Muscle Proteins; D014443:Tyrosine; D009195:Peroxidase
Duchenne Muscular Dystrophy (DMD); Golden Retriever Muscular Dystrophy (GRMD); Inflammation; Oxidative stress; Protein thiol oxidation; Taurine