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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 transcri...

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Autores principales: Phua, Wendy Wen Ting, Tan, Wei Ren, Yip, Yun Sheng, Hew, Ivan Dongzheng, Wee, Jonathan Wei Kiat, Cheng, Hong Sheng, Leow, Melvin Khee Shing, Wahli, Walter, Tan, Nguan Soon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084392/
https://www.ncbi.nlm.nih.gov/pubmed/32143325
http://dx.doi.org/10.3390/ijms21051747
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author Phua, Wendy Wen Ting
Tan, Wei Ren
Yip, Yun Sheng
Hew, Ivan Dongzheng
Wee, Jonathan Wei Kiat
Cheng, Hong Sheng
Leow, Melvin Khee Shing
Wahli, Walter
Tan, Nguan Soon
author_facet Phua, Wendy Wen Ting
Tan, Wei Ren
Yip, Yun Sheng
Hew, Ivan Dongzheng
Wee, Jonathan Wei Kiat
Cheng, Hong Sheng
Leow, Melvin Khee Shing
Wahli, Walter
Tan, Nguan Soon
author_sort Phua, Wendy Wen Ting
collection PubMed
description 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.
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spelling pubmed-70843922020-03-24 PPARβ/δ Agonism Upregulates Forkhead Box A2 to Reduce Inflammation in C2C12 Myoblasts and in Skeletal Muscle Phua, Wendy Wen Ting Tan, Wei Ren Yip, Yun Sheng Hew, Ivan Dongzheng Wee, Jonathan Wei Kiat Cheng, Hong Sheng Leow, Melvin Khee Shing Wahli, Walter Tan, Nguan Soon Int J Mol Sci Article 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. MDPI 2020-03-04 /pmc/articles/PMC7084392/ /pubmed/32143325 http://dx.doi.org/10.3390/ijms21051747 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Phua, Wendy Wen Ting
Tan, Wei Ren
Yip, Yun Sheng
Hew, Ivan Dongzheng
Wee, Jonathan Wei Kiat
Cheng, Hong Sheng
Leow, Melvin Khee Shing
Wahli, Walter
Tan, Nguan Soon
PPARβ/δ Agonism Upregulates Forkhead Box A2 to Reduce Inflammation in C2C12 Myoblasts and in Skeletal Muscle
title PPARβ/δ Agonism Upregulates Forkhead Box A2 to Reduce Inflammation in C2C12 Myoblasts and in Skeletal Muscle
title_full PPARβ/δ Agonism Upregulates Forkhead Box A2 to Reduce Inflammation in C2C12 Myoblasts and in Skeletal Muscle
title_fullStr PPARβ/δ Agonism Upregulates Forkhead Box A2 to Reduce Inflammation in C2C12 Myoblasts and in Skeletal Muscle
title_full_unstemmed PPARβ/δ Agonism Upregulates Forkhead Box A2 to Reduce Inflammation in C2C12 Myoblasts and in Skeletal Muscle
title_short PPARβ/δ Agonism Upregulates Forkhead Box A2 to Reduce Inflammation in C2C12 Myoblasts and in Skeletal Muscle
title_sort pparβ/δ agonism upregulates forkhead box a2 to reduce inflammation in c2c12 myoblasts and in skeletal muscle
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084392/
https://www.ncbi.nlm.nih.gov/pubmed/32143325
http://dx.doi.org/10.3390/ijms21051747
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