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GRMD Gene Expression in Skeletal and Cardiac Muscle: Insights into Molecular Pathways of Progression and Therapeutic Implications for DMD Cardiomyopathy
Author(s) -
Galindo Cristi,
BrinkmeyerLangford Candice,
Gupte Manisha,
Smith Holly,
Soslow Jon,
Sawyer Douglas,
Kornegay Joe,
Markham Larry
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1038.13
Subject(s) - duchenne muscular dystrophy , skeletal muscle , dystrophin , muscular dystrophy , cardiac muscle , itga7 , biology , cardiomyopathy , myocyte , mdx mouse , medicine , endocrinology , heart failure
Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. Progress has been made in defining the molecular basis and pathogenesis, but major gaps remain in understanding the differences in timing and progression of skeletal versus cardiac muscle dysfunction. To address this question, we analyzed skeletal and cardiac muscle microarrays from golden retriever dogs with muscular dystrophy (GRMD), a genetically homologous model for DMD. GRMD dogs exhibit a myopathic phenotype that closely approximates human disease. A total of 12 dogs, 3 each GRMD and controls at 6 and 12 months were assessed. With regard to the more severe skeletal muscle phenotype, GRMD dogs exhibited tissue‐ and age‐specific transcriptional profiles in keeping with the early‐onset “metabolic syndrome” seen on microarray analysis in human DMD. In GRMD skeletal but not cardiac muscle, 12 glycolytic enzymes were altered (up‐ or down‐regulated), 15 lysosomal genes were up‐regulated, and all but one of the enzymes that drive the TCA cycle and 13 electron transport chain transcripts were down‐regulated. On the other hand, a potential cardioprotective factor, brain‐derived neurotropic factor (BDNF) was elevated most profoundly in the cardiac muscle and serum samples of younger GRMD dogs. Taken together, we identified genes that could contribute to greater skeletal muscle involvement and others that might allow for a relative reciprocal sparing of the heart.Work supported by Fighting Duchenne Foundation (Markham), the MDA (Kornegay), and NIH (K01 HL121045)