title: Impaired insulin/IGF signaling in experimental alcohol-related myopathy.
abstract: Alcohol-related myopathy (Alc-M) is highly prevalent among heavy drinkers, although its pathogenesis is not well understood. We hypothesize that Alc-M is mediated by combined effects of insulin/IGF resistance and oxidative stress, similar to the effects of ethanol on liver and brain. We tested this hypothesis using an established model in which adult rats were pair-fed for 8 weeks with isocaloric diets containing 0% (N = 8) or 35.5% (N = 13) ethanol by caloric content. Gastrocnemius muscles were examined by histology, morphometrics, qRT-PCR analysis, and ELISAs. Chronic ethanol feeding reduced myofiber size and mRNA expression of IGF-1 polypeptide, insulin, IGF-1, and IGF-2 receptors, IRS-1, and IRS-2. Multiplex ELISAs demonstrated ethanol-associated inhibition of insulin, IRS-1, Akt, and p70S6K signaling, and increased activation of GSK-3β. In addition, ethanol-exposed muscles had increased 4-hydroxy-2-nonenal immunoreactivity, reflecting lipid peroxidation, and reduced levels of mitochondrial Complex IV, Complex V, and acetylcholinesterase. These results demonstrate that experimental Alc-M is associated with inhibition of insulin/IGF/IRS and downstream signaling that mediates metabolism and cell survival, similar to findings in alcoholic liver and brain degeneration. Moreover, the increased oxidative stress, which could be mediated by mitochondrial dysfunction, may have led to inhibition of acetylcholinesterase, which itself is sufficient to cause myofiber atrophy and degeneration.
authors.affiliation: Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA. va.nguyen87@gmail.com
authors.forename: Van Anh
authors.initials: VA
authors.lastname: Nguyen
authors.forename: Tran
authors.initials: T
authors.lastname: Le
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Silbermann
authors.forename: Fusun
authors.initials: F
authors.lastname: Gundogan
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
mesh_terms: D019973:Alcohol-Related Disorders / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004334:Drug Administration Schedule; D000431:Ethanol / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009135:Muscular Diseases / Q000139:chemically induced*; D018384:Oxidative Stress; D051381:Rats; D020318:Rats, Long-Evans; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D017527:Receptor, IGF Type 2; D000431:Ethanol; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1