Nuclear Factor-kappa B Signaling Inhibition for Sepsis-induced Skeletal Muscle Atrophy

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K16544
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55060:Emergency medicine-related
• Research Institution: Kobe University (2019-2021); Fukushima Medical University (2018)
• Principal Investigator: Ono Yuko 神戸大学, 医学部附属病院, 助教 (00745333)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 敗血症 / エンドトキシン血症 / Toll like receptor 4 / TAK-242

Outline of Final Research Achievements

Systemic inflammatory responses induced by LPS induce involuntary loss of skeletal muscle, termed muscle wasting. Currently, no drugs are available for the treatment of LPS-induced skeletal muscle wasting. We tested the effects of TAK-242, a Toll-like receptor 4 (TLR4)-specific signalling inhibitor, on myotube atrophy in vitro and muscle wasting in vivo induced by LPS. LPS treatment of murine C2C12 myotubes induced an inflammatory response and activated the proteolytic pathways, resulting in myotube atrophy. In mice, LPS injection increased the same inflammatory and proteolytic pathways in skeletal muscle and induced atrophy. Notably, pretreatment of cells or mice with TAK-242 reduced or reversed all the detrimental effects of LPS in vitro and in vivo. Collectively, our results indicate that pharmacological inhibition of TLR4 signalling may be a novel therapeutic intervention for endotoxemia-induced muscle wasting.

Free Research Field

骨格筋萎縮

Academic Significance and Societal Importance of the Research Achievements

現在世界では年間約4,890万人の敗血症患者が発生している (Rudd et al. Lancet. 2020) 。骨格筋萎縮は敗血症患者の生命予後、機能予後の両方を悪化させる。本研究により、LPS誘発性筋萎縮が、TLR4の薬理学的制御によって修正しうることが示された：本研究をとおして、多くの患者群に対し、これまでの理学療法や栄養療法とは異なる、新たな治療戦略の基盤となるデータが示された。