RRC ID 82080
Author Kanai M, Ganbaatar B, Endo I, Ohnishi Y, Teramachi J, Tenshin H, Higa Y, Hiasa M, Mitsui Y, Hara T, Masuda S, Yamagami H, Yamaguchi Y, Aihara KI, Sebe M, Tsutsumi R, Sakaue H, Matsumoto T, Abe M.
Title Inflammatory Cytokine-Induced Muscle Atrophy and Weakness Can Be Ameliorated by an Inhibition of TGF-β-Activated Kinase-1.
Journal Int J Mol Sci
Abstract Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-β-activated kinase-1 (TAK1) activation, inflammatory cytokine-induced muscle wasting may be ameliorated by the inhibition of TAK1 activity. The present study was undertaken to clarify whether TAK1 inhibition can ameliorate inflammation-induced muscle wasting. SKG/Jcl mice as an autoimmune arthritis animal model were treated with a small amount of mannan as an adjuvant to enhance the production of TNF-α and IL-1β. The increase in these inflammatory cytokines caused a reduction in muscle mass and strength along with an induction of arthritis in SKG/Jcl mice. Those changes in muscle fibers were mediated via the phosphorylation of TAK1, which activated the downstream signaling cascade via NF-κB, p38 MAPK, and ERK pathways, resulting in an increase in myostatin expression. Myostatin then reduced the expression of muscle proteins not only via a reduction in MyoD1 expression but also via an enhancement of Atrogin-1 and Murf1 expression. TAK1 inhibitor, LL-Z1640-2, prevented all the cytokine-induced changes in muscle wasting. Thus, TAK1 inhibition can be a new therapeutic target of not only joint destruction but also muscle wasting induced by inflammatory cytokines.
Volume 25(11)
Published 2024-5-24
DOI 10.3390/ijms25115715
PII ijms25115715
PMID 38891908
PMC PMC11172090
MeSH Animals Cytokines* / metabolism Disease Models, Animal Inflammation / drug therapy Inflammation / metabolism Inflammation / pathology Interleukin-1beta / metabolism MAP Kinase Kinase Kinases* / antagonists & inhibitors MAP Kinase Kinase Kinases* / metabolism Mice Muscle Proteins / metabolism Muscle Weakness / drug therapy Muscle Weakness / metabolism Muscle, Skeletal / drug effects Muscle, Skeletal / metabolism Muscle, Skeletal / pathology Muscular Atrophy* / drug therapy Muscular Atrophy* / etiology Muscular Atrophy* / metabolism Muscular Atrophy* / pathology Myostatin / antagonists & inhibitors Myostatin / metabolism NF-kappa B / metabolism Phosphorylation / drug effects Signal Transduction / drug effects Tripartite Motif Proteins / genetics Tripartite Motif Proteins / metabolism Tumor Necrosis Factor-alpha / metabolism Zearalenone / analogs & derivatives Zearalenone / pharmacology
Resource
Human and Animal Cells C2C12(RCB0987)