title: Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease.
abstract: Chronic kidney disease (CKD) and several other catabolic conditions are characterized by increased circulating inflammatory cytokines, defects in IGF-1 signaling, abnormal muscle protein metabolism, and progressive muscle atrophy. In these conditions, no reliable treatments successfully block the development of muscle atrophy. In mice with CKD, we found a 2- to 3-fold increase in myostatin expression in muscle. Its pharmacological inhibition by subcutaneous injections of an anti-myostatin peptibody into CKD mice (IC(50) ∼1.2 nM) reversed the loss of body weight (≈5-7% increase in body mass) and muscle mass (∼10% increase in muscle mass) and suppressed circulating inflammatory cytokines vs. results from CKD mice injected with PBS. Pharmacological myostatin inhibition also decreased the rate of protein degradation (16.38 ± 1.29%; P<0.05), increased protein synthesis in extensor digitorum longus muscles (13.21 ± 1.09%; P<0.05), markedly enhanced satellite cell function, and improved IGF-1 intracellular signaling. In cultured muscle cells, TNF-α increased myostatin expression via a NF-κB-dependent pathway, whereas muscle cells exposed to myostatin stimulated IL-6 production via p38 MAPK and MEK1 pathways. Because IL-6 stimulates muscle protein breakdown, we conclude that CKD increases myostatin through cytokine-activated pathways, leading to muscle atrophy. Myostatin antagonism might become a therapeutic strategy for improving muscle growth in CKD and other conditions with similar characteristics.
authors.affiliation: Nephrology Division, Baylor College of Medicine, Houston, Texas, USA 77030, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.forename: Vik
authors.initials: V
authors.lastname: Rajan
authors.forename: Eugene
authors.initials: E
authors.lastname: Lin
authors.forename: Zhaoyong
authors.initials: Z
authors.lastname: Hu
authors.forename: H Q
authors.initials: HQ
authors.lastname: Han
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhou
authors.forename: Yanping
authors.initials: Y
authors.lastname: Song
authors.forename: Hosung
authors.initials: H
authors.lastname: Min
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
mesh_terms: D000818:Animals; D002460:Cell Line; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000276:immunology; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000378:metabolism; D055435:Myostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015850:Interleukin-6; D055435:Myostatin; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D007334:Insulin-Like Growth Factor I