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66Skeletal muscle PGC-1alpha is required for maintaining an acute LPS-induced TNFalpha response.
Olesen J; Larsson S; Iversen N; Yousafzai S; Hellsten Y; Pilegaard H
PLoS One 2012; 7(2): e32222
PubMed ID: 22384185

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

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