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Regulation of the calpain and ubiquitin proteasome system in a canine model of muscular dystrophy with myostatin inhibition
Author(s) -
Cotten Steven W.,
Wadosky Kristine M.,
Bogan Dan,
Kornegay Joe N.,
Willis Monte S.
Publication year - 2012
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.26.1_supplement.478.3
Subject(s) - myostatin , duchenne muscular dystrophy , muscular dystrophy , ubiquitin , endocrinology , medicine , skeletal muscle , biology , calpain , dystrophin , proteasome , microbiology and biotechnology , genetics , biochemistry , enzyme , gene
Recent studies have suggested that inhibiting the protein myostatin, a negative regulator of skeletal muscle mass, may improve outcomes in patients with Duchenne Muscular Dystrophy (DMD) by enhancing muscle mass. We tested this hypothesis by crossing the golden retriever muscular dystrophy (GRMD) dog with the whippet dog having a homozygous mutation for the myostatin‐null allele (Mstn −/−, the so‐called bully whippet). Surprisingly, individuals with affected muscular dystrophy and decreased myostatin demonstrated an accelerated physical decline compared to related GRMD affected dogs with full myostatin. To examine mechanisms responsible for this accelerated decline, we measured novel ubiquitin ligases, proteasome subunits, and calpain 1/2 by real time PCR in the cranial sartorius and vastus lateralis muscles to determine the effects on the ubiquitin proteasome in wild type, GRMD, and GRMD/Myostatin +/− dogs (N=10 total). While affected GRMD dogs had decreases in the ubiquitin ligases MuRF1, Atrogin‐1, RNF25, RNF11, and CHIP, affected GRMD dogs with decreased myostatin exhibited enhanced levels of MuRF1 and Atrogin‐1. These studies suggest a role of myostatin in the disease progression of GRMD, which may involve key components of the ubiquitin proteasome system involved in the turnover of sarcomere proteins in the skeletal muscle.