PPARβ/δ Agonism Upregulates Forkhead Box A2 to Reduce Inflammation in C2C12 Myoblasts and in Skeletal Muscle.
Daily activities expose muscles to innumerable impacts, causing accumulated tissue damage and inflammation that impairs muscle recovery and function, yet the mechanism modulating the inflammatory response in muscles remains unclear. Our study suggests that Forkhead box A2 (FoxA2), a pioneer transcription factor, has a predominant role in the inflammatory response during skeletal muscle injury. FoxA2 expression in skeletal muscle is upregulated by fatty acids and peroxisome proliferator-activated receptors (PPARs) but is refractory to insulin and glucocorticoids. Using PPARβ/δ agonist GW501516 upregulates FoxA2, which in turn, attenuates the production of proinflammatory cytokines and reduces the infiltration of CD45+ immune cells in two mouse models of muscle inflammation, systemic LPS and intramuscular injection of carrageenan, which mimic localized exercise-induced inflammation. This reduced local inflammatory response limits tissue damage and restores muscle tetanic contraction. In line with these results, a deficiency in either PPARβ/δ or FoxA2 diminishes the action of the PPARβ/δ agonist GW501516 to suppress an aggravated inflammatory response. Our study suggests that FoxA2 in skeletal muscle helps maintain homeostasis, acting as a gatekeeper to maintain key inflammation parameters at the desired level upon injury. Therefore, it is conceivable that certain myositis disorders or other forms of painful musculoskeletal diseases may benefit from approaches that increase FoxA2 activity in skeletal muscle.
['Phua|Wendy Wen Ting|WWT|', 'Tan|Wei Ren|WR|', 'Yip|Yun Sheng|YS|', 'Hew|Ivan Dongzheng|ID|', 'Wee|Jonathan Wei Kiat|JWK|', 'Cheng|Hong Sheng|HS|0000-0001-9745-7872', 'Leow|Melvin Khee Shing|MKS|0000-0002-2837-5889', 'Wahli|Walter|W|0000-0002-5966-9089', 'Tan|Nguan Soon|NS|0000-0003-0136-7341']
D000818:Animals D016207:Cytokines D005786:Gene Expression Regulation D005938:Glucocorticoids D057809:HEK293 Cells D051542:Hepatocyte Nuclear Factor 3-beta D006706:Homeostasis D006801:Humans D007249:Inflammation D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018482:Muscle, Skeletal D032446:Myoblasts D047494:PPAR delta D048068:PPAR-beta D015398:Signal Transduction D013844:Thiazoles D015533:Transcriptional Activation D015854:Up-Regulation
Forkhead box A2 muscle inflammation tetanic contraction peroxisome proliferator-activated receptors β/δ