PPAR‐γ activation inhibits TNF‐α induced NF‐κB activity in skeletal muscle

Abstract

Peroxisome proliferator‐activated receptor γ (PPARγ) has anti‐inflammatory properties which, in part, rely on its ability to modulate signaling by the cytokine‐inducible transcription factor NF‐κB. NF‐κB activation has been causally related to skeletal muscle atrophy, which is a characteristic of several chronic inflammatory diseases. The goal of this study was to evaluate if PPARγ activation affects TNF‐α induced NF‐κB activity in skeletal muscle cells. C2C12 Myoblasts with a genomically integrated NF‐κB luciferase reporter construct were differentiated during 6 days into myotubes. TNFα (1ng/ml, 4h) induced an 8‐fold increase in NF‐κB transcriptional activity. Pre‐treatment of the myotubes with the specific PPARγ agonist rosiglitazone significantly lowered TNFα induced NF‐κB transcriptional activity in a dose and time dependent fashion, with a maximal inhibitory effect of 80% (150 μM, 1h pre‐incubation). Similar effects were observed when a structurally unrelated PPARγ agonist was applied, or in response to IL‐1β‐induced NF‐κB activation. In addition, a significant decrease in mRNA levels of the NF‐κB target genes ICAM‐1 and KC was observed. These results demonstrate that NF‐κB activation by pro‐inflammatory cytokines in skeletal muscle can be suppressed by PPARγ agonists, which may be a new venue for therapeutic targeting of skeletal muscle atrophy.This abstract was sponsored by Numico Research