title: GRMD cardiac and skeletal muscle metabolism gene profiles are distinct.
abstract: Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which codes for the dystrophin protein. While progress has been made in defining the molecular basis and pathogenesis of DMD, major gaps remain in understanding mechanisms that contribute to the marked delay in cardiac compared to skeletal muscle dysfunction.
  
  
  
  To address this question, we analyzed cardiac and skeletal muscle tissue microarrays from golden retriever muscular dystrophy (GRMD) dogs, a genetically and clinically homologous model for DMD. A total of 15 dogs, 3 each GRMD and controls at 6 and 12 months plus 3 older (47-93 months) GRMD dogs, were assessed.
  
  
  
  GRMD dogs exhibited tissue- and age-specific transcriptional profiles and enriched functions in skeletal but not cardiac muscle, consistent with a "metabolic crisis" seen with DMD microarray studies. Most notably, dozens of energy production-associated molecules, including all of the TCA cycle enzymes and multiple electron transport components, were down regulated. Glycolytic and glycolysis shunt pathway-associated enzymes, such as those of the anabolic pentose phosphate pathway, were also altered, in keeping with gene expression in other forms of muscle atrophy. On the other hand, GRMD cardiac muscle genes were enriched in nucleotide metabolism and pathways that are critical for neuromuscular junction maintenance, synaptic function and conduction.
  
  
  
  These findings suggest differential metabolic dysfunction may contribute to distinct pathological phenotypes in skeletal and cardiac muscle.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2200 Pierce Avenue, 359A Preston Research Building, Nashville, TN, 37232, USA.|Department of Pediatrics, Division of Pediatric Cardiology, Vanderbilt University Medical Center, Nashville, USA.
authors.forename: Larry W
authors.initials: LW
authors.lastname: Markham
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA.
authors.forename: Candice L
authors.initials: CL
authors.lastname: Brinkmeyer-Langford
authors.affiliation: Department of Pediatrics, Division of Pediatric Cardiology, Vanderbilt University Medical Center, Nashville, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Soslow
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2200 Pierce Avenue, 359A Preston Research Building, Nashville, TN, 37232, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Gupte
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2200 Pierce Avenue, 359A Preston Research Building, Nashville, TN, 37232, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA.
authors.forename: Joe N
authors.initials: JN
authors.lastname: Kornegay
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2200 Pierce Avenue, 359A Preston Research Building, Nashville, TN, 37232, USA. Cristi.L.Galindo@Vanderbilt.edu.
authors.forename: Cristi L
authors.initials: CL
authors.lastname: Galindo
mesh_terms: D000818:Animals; D004283:Dog Diseases / Q000235:genetics* / Q000378:metabolism; D004285:Dogs; D020869:Gene Expression Profiling; D006019:Glycolysis; D018482:Muscle, Skeletal / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D010641:Phenotype
keywords: BDNF; Cardiac; Duchenne; Dystrophin; Metabolism; Muscular dystrophy