Identification of the mechanism of sepsis induced muscle wasting and potential pharmacological treatment

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K20349
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Emergency medicine
• Research Institution: Fukushima Medical University
• Principal Investigator: Ono Yuko 福島県立医科大学, 医学部 救急医療学講座, 助教 (00745333)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 骨格筋分化 / 敗血症 / Toll like receptor 4 / TAK 242 / TNFα

Outline of Final Research Achievements

The purpose of this study was to evaluate the effect of lipopolysaccharide (LPS) on skeletal muscle myogenesis.
LPS dose-dependently and significantly decreased the formation of C2C12 myotubes and the expression of myosin heavy chain II, myogenin, and MyoD, and increased NF-κB DNA-binding activity and myostatin expression. Both TAK-242, a specific inhibitor of Toll-like receptor 4 signaling and anti-TNF-α antibody reduced the LPS-induced increase in NF-κB DNA-binding activity, downregulation of myogenic regulatory factors, and upregulation of myostatin, thereby partially rescuing the impairment of myogenesis. Our data suggest that LPS inhibits myogenic differentiation via a TLR4 and NF-κB-dependent pathway and an autocrine/paracrine TNF-α-induced pathway. These pathways may be involved in the development of muscle wasting caused by sepsis or metabolic endotoxemia. This study shows novel molecular basis of sepsis induced muscle wasting and the therapeutic target for this etiology.

Free Research Field

救急医学、薬理学