title: Genetic myostatin decrease in the golden retriever muscular dystrophy model does not significantly affect the ubiquitin proteasome system despite enhancing the severity of disease.
abstract: Recent studies suggest that inhibiting the protein myostatin, a negative regulator of skeletal muscle mass, may improve outcomes in patients with Duchenne muscular dystrophy by enhancing muscle mass. When the dystrophin-deficient golden retriever muscular dystrophy (GRMD) dog was bred with whippets having a heterozygous mutation for the myostatin gene, affected GRMD dogs with decreased myostatin (GRippets) demonstrated an accelerated physical decline compared to related affected GRMD dogs with full myostatin. To examine the role of the ubiquitin proteasome and calpain systems in this accelerated decline, we determined the expression of the muscle ubiquitin ligases MuRF1, Atrogin-1, RNF25, RNF11, and CHIP: the proteasome subunits PSMA6, PSMB4, and PSME1: and calpain 1/2 by real time PCR in the cranial sartorius and vastus lateralis muscles in control, affected GRMD, and GRippet dogs. While individual affected GRMD and GRippet dogs contributed to an increased variability seen in ubiquitin ligase expression, neither group was significantly different from the control group. The affected GRMD dogs demonstrated significant increases in caspase-like and trypsin-like activity in the cranial sartorius; however, all three proteasome activities in the GRippet muscles did not differ from controls. Increased variability in calpain 1 and calpain 2 expression and activity in the affected GRMD and GRippet groups were identified, but no statistical differences from the control group were seen. These studies suggest a role of myostatin in the disease progression of GRMD, which does not significantly involve key components of the ubiquitin proteasome and calpain systems involved in the protein quality control of sarcomere and other structural skeletal muscle proteins.
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center Columbus, OH, USA ; Department of Pathology and Laboratory Medicine, University of North Carolina Chapel Hill, NC, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Cotten
authors.affiliation: Department of Veterinary Integrative Biosciences (Mail Stop 4458), College of Veterinary Medicine, Texas A&M University College Station, TX, USA.
authors.forename: Joe N
authors.initials: JN
authors.lastname: Kornegay
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina Chapel Hill, NC, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bogan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina Chapel Hill, NC, USA.
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Wadosky
authors.affiliation: Departments of Medicine, Pharmacology, Cell and Developmental Biology, University of North Carolina Chapel Hill, NC, USA ; McAllister Heart Institute, University of North Carolina Chapel Hill, USA.
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina Chapel Hill, NC, USA ; McAllister Heart Institute, University of North Carolina Chapel Hill, USA.
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
keywords: Ubiquitin; calpain; dystrophin; muscular dystrophy; myostatin; proteasome