title: Sparing of the dystrophin-deficient cranial sartorius muscle is associated with classical and novel hypertrophy pathways in GRMD dogs.
abstract: Both Duchenne and golden retriever muscular dystrophy (GRMD) are caused by dystrophin deficiency. The Duchenne muscular dystrophy sartorius muscle and orthologous GRMD cranial sartorius (CS) are relatively spared/hypertrophied. We completed hierarchical clustering studies to define molecular mechanisms contributing to this differential involvement and their role in the GRMD phenotype. GRMD dogs with larger CS muscles had more severe deficits, suggesting that selective hypertrophy could be detrimental. Serial biopsies from the hypertrophied CS and other atrophied muscles were studied in a subset of these dogs. Myostatin showed an age-dependent decrease and an inverse correlation with the degree of GRMD CS hypertrophy. Regulators of myostatin at the protein (AKT1) and miRNA (miR-539 and miR-208b targeting myostatin mRNA) levels were altered in GRMD CS, consistent with down-regulation of myostatin signaling, CS hypertrophy, and functional rescue of this muscle. mRNA and proteomic profiling was used to identify additional candidate genes associated with CS hypertrophy. The top-ranked network included α-dystroglycan and like-acetylglucosaminyltransferase. Proteomics demonstrated increases in myotrophin and spectrin that could promote hypertrophy and cytoskeletal stability, respectively. Our results suggest that multiple pathways, including decreased myostatin and up-regulated miRNAs, α-dystroglycan/like-acetylglucosaminyltransferase, spectrin, and myotrophin, contribute to hypertrophy and functional sparing of the CS. These data also underscore the muscle-specific responses to dystrophin deficiency and the potential deleterious effects of differential muscle involvement.
authors.affiliation: Department of Integrative Systems Biology, George Washington University School of Medicine, Washington, District of Columbia; Research Center for Genetic Medicine, Children's National Medical Center, Washington, District of Columbia.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nghiem
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Priya
authors.initials: P
authors.lastname: Mittal
authors.forename: Kristy J
authors.initials: KJ
authors.lastname: Brown
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Schatzberg
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ghimbovschi
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Wang
authors.forename: Joe N
authors.initials: JN
authors.lastname: Kornegay
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D004285:Dogs; D049030:Dystroglycans / Q000378:metabolism; D016189:Dystrophin / Q000172:deficiency* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006031:Glycosylation; D006984:Hypertrophy; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000473:pathology*; D055435:Myostatin / Q000378:metabolism; D009929:Organ Size; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013049:Spectrin / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D049411:Utrophin / Q000378:metabolism
chemical_list: D016189:Dystrophin; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D055435:Myostatin; D049411:Utrophin; C065700:myotrophin; D013049:Spectrin; D049030:Dystroglycans; D051057:Proto-Oncogene Proteins c-akt