Skeletal Muscle PGC-1α Is Required for Maintaining an Acute LPS-Induced TNFα Response

Many lifestyle-related diseases are associated with low-grade inflammation and peroxisome proliferator activated receptor gamma coactivator (PGC)-1 alpha has been suggested to be protective against low-grade inflammation. However, whether these anti-inflammatory properties affect acute inflammation is not known. The aim of the present study was therefore to investigate the role of muscle PGC-1 alpha in acute inflammation. Quadriceps muscles were removed from 10-week old whole body PGC-1 alpha knockout (KO), muscle specific PGC-1 alpha KO (MKO) and muscle-specific PGC-1 alpha overexpression mice (TG), 2 hours after an intraperitoneal injection of either 0.8 mu g LPS/g body weight or saline. Basal TNF alpha mRNA content was lower in skeletal muscle of whole body PGC-1 alpha KO mice and in accordance TG mice showed increased TNF alpha mRNA and protein level relative to WT, indicating a possible PGC-1 alpha mediated regulation of TNF alpha. Basal p65 phosphorylation was increased in TG mice possibly explaining the elevated TNF alpha expression in these mice. Systemically, TG mice had reduced basal plasma TNF alpha levels compared with WT suggesting a protective effect against systemic low-grade inflammation in these animals. While TG mice reached similar TNF alpha levels as WT and showed more marked induction in plasma TNF alpha than WT after LPS injection, MKO PGC-1 alpha mice had a reduced plasma TNF alpha and skeletal muscle TNF alpha mRNA response to LPS. In conclusion, the present findings suggest that PGC-1 alpha enhances basal TNF alpha expression in skeletal muscle and indicate that PGC-1 alpha does not exert anti-inflammatory effects during acute inflammation. Lack of skeletal muscle PGC-1 alpha seems however to impair the acute TNF alpha response, which may reflect a phenotype more susceptible to infections as also observed in type 2 diabetes patients.