title: Lack of MG53 in human heart precludes utility as a biomarker of myocardial injury or endogenous cardioprotective factor.
abstract: OBJECTIVE
  Mitsugumin-53 (MG53/TRIM72) is an E3-ubiquitin ligase that rapidly accumulates at sites of membrane injury and plays an important role in membrane repair of skeletal and cardiac muscle. MG53 has been implicated in cardiac ischaemia-reperfusion injury, and serum MG53 provides a biomarker of skeletal muscle injury in the mdx mouse model of Duchenne muscular dystrophy. We evaluated the clinical utility of MG53 as a biomarker of myocardial injury.
  
  
  RESULTS
  We performed Langendorff ischaemia-reperfusion injury on wild-type and dysferlin-null murine hearts, using dysferlin deficiency to effectively model more severe outcomes from cardiac ischaemia-reperfusion injury. MG53 released into the coronary effluent correlated strongly and significantly (r = 0.79-0.85, P < 0.0001) with functional impairment after ischaemic injury. We initiated a clinical trial in paediatric patients undergoing corrective heart surgery, the first study of MG53 release with myocardial injury in humans. Unexpectedly, we reveal although MG53 is robustly expressed in rat and mouse hearts, MG53 is scant to absent in human, ovine, or porcine hearts. Absence of MG53 in 11 human heart specimens was confirmed using three separate antibodies to MG53, each subject to epitope mapping and confirmed immunospecificity using MG53-deficient muscle cells.
  
  
  CONCLUSIONS
  MG53 is an effective biomarker of myocardial injury and dysfunction in murine hearts. However, MG53 is not expressed in human heart and therefore does not hold utility as a clinical biomarker of myocardial injury. Although cardioprotective roles for endogenous myocardial MG53 cannot be extrapolated from rodents to humans, potential therapeutic application of recombinant MG53 for myocardial membrane injury prevails.
authors.affiliation: Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, Australia frances.lemckert@sydney.edu.au.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Lemckert
authors.affiliation: Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Bournazos
authors.affiliation: Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, Australia.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Eckert
authors.affiliation: Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, Australia.
authors.forename: Manuel
authors.initials: M
authors.lastname: Kenzler
authors.affiliation: Kid's Hearts Research, Heart Centre for Children, The Children's Hospital at Westmead, Westmead 2145, Australia.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Hawkes
authors.affiliation: Kid's Hearts Research, Heart Centre for Children, The Children's Hospital at Westmead, Westmead 2145, Australia.
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Butler
authors.affiliation: Kid's Hearts Research, Heart Centre for Children, The Children's Hospital at Westmead, Westmead 2145, Australia Discipline of Paediatrics and Child Health, University of Sydney, Children's Hospital at Westmead Clinical School, Westmead 2145, Australia.
authors.forename: Bradley
authors.initials: B
authors.lastname: Ceely
authors.affiliation: Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, Australia Discipline of Paediatrics and Child Health, University of Sydney, Children's Hospital at Westmead Clinical School, Westmead 2145, Australia.
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.affiliation: Kid's Hearts Research, Heart Centre for Children, The Children's Hospital at Westmead, Westmead 2145, Australia Discipline of Paediatrics and Child Health, University of Sydney, Children's Hospital at Westmead Clinical School, Westmead 2145, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Winlaw
authors.affiliation: Kid's Hearts Research, Heart Centre for Children, The Children's Hospital at Westmead, Westmead 2145, Australia Discipline of Paediatrics and Child Health, University of Sydney, Children's Hospital at Westmead Clinical School, Westmead 2145, Australia.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Egan
authors.affiliation: Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, Australia Discipline of Paediatrics and Child Health, University of Sydney, Children's Hospital at Westmead Clinical School, Westmead 2145, Australia.
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Cooper
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000503:physiopathology; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D012756:Sheep; D013552:Swine; D000070584:Tripartite Motif Proteins; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; C538824:MG53 protein, mouse; D008565:Membrane Proteins; D009124:Muscle Proteins; C558399:TRIM72 protein, human; C000604080:TRIM72 protein, rat; D000070584:Tripartite Motif Proteins; D033921:Vesicular Transport Proteins
keywords: Biomarker of myocardial injury; Ischaemia–reperfusion injury; Ischaemic preconditioning/postconditioning; MG53; TRIM72