title: Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1.
abstract: Skeletal muscle atrophy, referred to as sarcopenia, is often observed in chronic kidney disease (CKD) patients, especially in patients who are undergoing hemodialysis. The purpose of this study was to determine whether uremic toxins are involved in CKD-related skeletal muscle atrophy. Among six protein-bound uremic toxins, indole containing compounds, indoxyl sulfate (IS) significantly inhibited proliferation and myotube formation in C2C12 myoblast cells. IS increased the factors related to skeletal muscle breakdown, such as reactive oxygen species (ROS) and inflammatory cytokines (TNF-α, IL-6 and TGF-β1) in C2C12 cells. IS also enhanced the production of muscle atrophy-related genes, myostatin and atrogin-1. These effects induced by IS were suppressed in the presence of an antioxidant or inhibitors of the organic anion transporter and aryl hydrocarbon receptor. The administered IS was distributed to skeletal muscle and induced superoxide production in half-nephrectomized (1/2 Nx) mice. The chronic administration of IS significantly reduced the body weights accompanied by skeletal muscle weight loss. Similar to the in vitro data, IS induced the expression of myostatin and atrogin-1 in addition to increasing the production of inflammatory cytokines by enhancing oxidative stress in skeletal muscle. These data suggest that IS has the potential to accelerate skeletal muscle atrophy by inducing oxidative stress-mediated myostatin and atrogin-1 expression.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Enoki
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.|Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, Kumamoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.
authors.forename: Riho
authors.initials: R
authors.lastname: Arake
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.
authors.forename: Ryusei
authors.initials: R
authors.lastname: Sugimoto
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Imafuku
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Tominaga
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.|Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, Kumamoto, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ishima
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kotani
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Department of Nephrology, Akebono Clinic, Kumamoto, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Nephrology, Akebono Clinic, Kumamoto, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Fukagawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Kumamoto, Japan.|DDS Research Institute, Sojo University, Kumamoto, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.|Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, Kumamoto, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D007200:Indican / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000187:drug effects; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D032446:Myoblasts / Q000187:drug effects; D055435:Myostatin / Q000096:biosynthesis* / Q000235:genetics; D009392:Nephrectomy; D009929:Organ Size / Q000187:drug effects; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis* / Q000235:genetics; D055948:Sarcopenia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014511:Uremia / Q000378:metabolism / Q000473:pathology; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000975:Antioxidants; D016207:Cytokines; C525912:Mstn protein, mouse; D009124:Muscle Proteins; D055435:Myostatin; D027361:Organic Anion Transporters; D018336:Receptors, Aryl Hydrocarbon; D013481:Superoxides; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D007200:Indican