Inflammatory Cytokine-Induced Muscle Atrophy and Weakness Can Be Ameliorated by an Inhibition of TGF-β-Activated Kinase-1

• Published in: International journal of molecular sciences Vol. 25; no. 11; p. 5715
• Main Authors: Kanai, Mai, Ganbaatar, Byambasuren, Endo, Itsuro, Ohnishi, Yukiyo, Teramachi, Jumpei, Tenshin, Hirofumi, Higa, Yoshiki, Hiasa, Masahiro, Mitsui, Yukari, Hara, Tomoyo, Masuda, Shiho, Yamagami, Hiroki, Yamaguchi, Yuki, Aihara, Ken-ichi, Sebe, Mayu, Tsutsumi, Rie, Sakaue, Hiroshi, Matsumoto, Toshio, Abe, Masahiro
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.06.2024; MDPI
• Subjects: Analysis; Arthritis; Atrophy; Cytokines; Genes; IL-1β; Inflammation; Kinases; Muscle proteins; Musculoskeletal system; MyoD1; myostatin; Proteins; Rheumatoid arthritis; TAK1 inhibitor; TNF-α; Transforming growth factors; Tumor necrosis factor; Japan
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25115715

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.