title: Prevention of skeletal muscle atrophy in vitro using anti-ubiquitination oligopeptide carried by atelocollagen.
abstract: Skeletal muscle atrophy occurs when the rate of protein degradation exceeds that of protein synthesis in various catabolic conditions, such as fasting, disuse, aging, and chronic diseases. Insulin-like growth factor-1 (IGF-1) signaling stimulates muscle growth and suppresses muscle protein breakdown. In atrophied muscles, ubiquitin ligase, Cbl-b, increases and stimulates the ubiquitination and degradation of IRS-1, an intermediate in IGF-1 signaling pathway, resulting in IGF-1 resistance. In this study, we evaluated the efficacy of atelocollagen (ATCOL)-transported anti-ubiquitination oligopeptide (Cblin: Cbl-b inhibitor) (consisting of tyrosine phosphorylation domain of IRS-1) in starved C2C12 myotubes. The amount of IRS-1 protein was lower in starved versus unstarved myotubes. The Cblin-ATCOL complex inhibited IRS-1 degradation in a concentration-dependent manner. Myotubes incubated with Cblin-ATCOL complex showed significant resistance to starvation-induced atrophy (p<0.01). Furthermore, the Cblin-ATCOL complex significantly inhibited any decrease in Akt phosphorylation (p<0.01) and localization of FOXO3a to the nucleus in starved myotubes. These results suggest that Cblin prevented starvation-induced C2C12 myotube atrophy by maintaining the IGF-1/Akt/FOXO signaling. Therefore, attachment of anti-ubiquitination oligopeptide, Cblin, to ATCOL enhances its delivery to myotubes and could be a potentially effective strategy in the treatment of atrophic myopathies.
authors: Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan; Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. Electronic address: kamo@tokushima-u.ac.jp.
authors: Nobuhiko
authors: N
authors: Kawai
authors: Graduate School of Fisheries Science and Environmental Studies, Nagasaki University, Nagasaki, Japan.
authors: Katsuya
authors: K
authors: Hirasaka
authors: Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Tasuku
authors: T
authors: Maeda
authors: Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Marie
authors: M
authors: Haruna
authors: Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan; Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Chieko
authors: C
authors: Shiota
authors: Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Arisa
authors: A
authors: Ochi
authors: Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Tomoki
authors: T
authors: Abe
authors: Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Shohei
authors: S
authors: Kohno
authors: Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Ayako
authors: A
authors: Ohno
authors: Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Sigetada
authors: S
authors: Teshima-Kondo
authors: Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Hiroyo
authors: H
authors: Mori
authors: Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Eiji
authors: E
authors: Tanaka
authors: Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors: Takeshi
authors: T
authors: Nikawa
mesh_terms: D000818:Animals; D003094:Collagen / Q000494:pharmacology*; D016895:Culture Media, Serum-Free; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology*; D009133:Muscular Atrophy / Q000517:prevention & control*; D009842:Oligopeptides / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D050721:Proto-Oncogene Proteins c-cbl; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects*
chemical_list: D016895:Culture Media, Serum-Free; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D009842:Oligopeptides; C059821:atelocollagen; D007334:Insulin-Like Growth Factor I; D003094:Collagen; D050721:Proto-Oncogene Proteins c-cbl
keywords: IGF-1 signaling; Muscle atrophy; Starvation; Ubiquitin ligase