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Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo

A Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects...

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Autores principales: Oh, Tae Seok, Hutchins, Damian C., Mainali, Rabina, Goslen, Kevin H., Quinn, Matthew A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898833/
https://www.ncbi.nlm.nih.gov/pubmed/35265064
http://dx.doi.org/10.3389/fimmu.2022.748375
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author Oh, Tae Seok
Hutchins, Damian C.
Mainali, Rabina
Goslen, Kevin H.
Quinn, Matthew A.
author_facet Oh, Tae Seok
Hutchins, Damian C.
Mainali, Rabina
Goslen, Kevin H.
Quinn, Matthew A.
author_sort Oh, Tae Seok
collection PubMed
description A Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects outside the immune system still remain limited, particularly in the muscle. Therefore, we endeavored to determine if itaconate signaling impacts muscle differentiation. Utilizing the well-established C2C12 model of in vitro myogenesis, we evaluated the effects of itaconate and its derivatives on transcriptional and protein markers of muscle differentiation as well as mitochondrial function. We found itaconate and the derivatives dimethyl itaconate and 4-octyl itaconate disrupt differentiation media-induced myogenesis. A primary biological effect of itaconate is a succinate dehydrogenase (SDH) inhibitor. We find the SDH inhibitors dimethyl malonate and harzianopyridone phenocopie the anti-myogenic effects of itaconate. Furthermore, we find treatment with exogenous succinate results in blunted myogenesis. Together our data indicate itaconate and its derivatives interfere with in vitro myogenesis, potentially through inhibition of SDH and subsequent succinate accumulation. We also show 4-octyl itaconate suppresses injury-induced MYOG expression in vivo. More importantly, our findings suggest the therapeutic potential of itaconate, and its derivatives could be limited due to deleterious effects on myogenesis.
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spelling pubmed-88988332022-03-08 Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo Oh, Tae Seok Hutchins, Damian C. Mainali, Rabina Goslen, Kevin H. Quinn, Matthew A. Front Immunol Immunology A Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects outside the immune system still remain limited, particularly in the muscle. Therefore, we endeavored to determine if itaconate signaling impacts muscle differentiation. Utilizing the well-established C2C12 model of in vitro myogenesis, we evaluated the effects of itaconate and its derivatives on transcriptional and protein markers of muscle differentiation as well as mitochondrial function. We found itaconate and the derivatives dimethyl itaconate and 4-octyl itaconate disrupt differentiation media-induced myogenesis. A primary biological effect of itaconate is a succinate dehydrogenase (SDH) inhibitor. We find the SDH inhibitors dimethyl malonate and harzianopyridone phenocopie the anti-myogenic effects of itaconate. Furthermore, we find treatment with exogenous succinate results in blunted myogenesis. Together our data indicate itaconate and its derivatives interfere with in vitro myogenesis, potentially through inhibition of SDH and subsequent succinate accumulation. We also show 4-octyl itaconate suppresses injury-induced MYOG expression in vivo. More importantly, our findings suggest the therapeutic potential of itaconate, and its derivatives could be limited due to deleterious effects on myogenesis. Frontiers Media S.A. 2022-02-21 /pmc/articles/PMC8898833/ /pubmed/35265064 http://dx.doi.org/10.3389/fimmu.2022.748375 Text en Copyright © 2022 Oh, Hutchins, Mainali, Goslen and Quinn https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Oh, Tae Seok
Hutchins, Damian C.
Mainali, Rabina
Goslen, Kevin H.
Quinn, Matthew A.
Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo
title Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo
title_full Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo
title_fullStr Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo
title_full_unstemmed Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo
title_short Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo
title_sort itaconate and its derivatives repress early myogenesis in vitro and in vivo
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898833/
https://www.ncbi.nlm.nih.gov/pubmed/35265064
http://dx.doi.org/10.3389/fimmu.2022.748375
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