Indoxyl sulfate inhibits muscle cell differentiation via Myf6/MRF4 and MYH2 downregulation
ABSTRACT Background Chronic kidney disease (CKD) is associated with a significant decrease in muscle strength and mass, possibly related to muscle cell damage by uremic toxins. Here, we studied in vitro and in vivo the effect of indoxyl sulfate (IS), an indolic uremic toxin, on myoblast proliferatio...
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| creator | Bataille, Stanislas McKay, Nathalie Koppe, Laetitia Beau, Alice Benoit, Bérengère Bartoli, Marc Da Silva, Nathalie Poitevin, Stéphane Aniort, Julien Chermiti, Rania Burtey, Stéphane Dou, Laetitia |
| description | ABSTRACT
Background
Chronic kidney disease (CKD) is associated with a significant decrease in muscle strength and mass, possibly related to muscle cell damage by uremic toxins. Here, we studied in vitro and in vivo the effect of indoxyl sulfate (IS), an indolic uremic toxin, on myoblast proliferation, differentiation and expression of myogenic regulatory factors (MRF)—myoblast determination protein 1 (MyoD1), myogenin (Myog), Myogenic Factor 5 (Myf5) and myogenic regulatory factor 4 (Myf6/MRF4)—and expression of myosin heavy chain, Myh2.
Methods
C2C12 myoblasts were cultured in vitro and differentiated in myotubes for 7 days in the presence of IS at a uremic concentration of 200 µM. Myocytes morphology and differentiation was analyzed after hematoxylin-eosin staining. MRF genes’ expression was studied using reverse transcription polymerase chain reaction in myocytes and 5/6th nephrectomized mice muscle. Myf6/MRF4 protein expression was studied using enzyme-linked immunosorbent assay; MYH2 protein expression was studied using western blotting. The role of Aryl Hydrocarbon Receptor (AHR)—the cell receptor of IS—was studied by adding an AHR inhibitor into the cell culture milieu.
Results
In the presence of IS, the myotubes obtained were narrower and had fewer nuclei than control myotubes. The presence of IS during differentiation did not modify the gene expression of the MRFs Myf5, MyoD1 and Myog, but induced a decrease in expression of Myf6/MRF4 and MYH2 at the mRNA and the protein level. AHR inhibition by CH223191 did not reverse the decrease in Myf6/MRF4 mRNA expression induced by IS, which rules out the implication of the ARH genomic pathway. In 5/6th nephrectomized mice, the Myf6/MRF4 gene was down-regulated in striated muscles.
Conclusion
In conclusion, IS inhibits Myf6/MRF4 and MYH2 expression during differentiation of muscle cells, which could lead to a defect in myotube structure. Through these new mechanisms, IS could participate in muscle atrophy observed in CKD. |
| doi_str_mv | 10.1093/ndt/gfad123 |
| format | Article |
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Background
Chronic kidney disease (CKD) is associated with a significant decrease in muscle strength and mass, possibly related to muscle cell damage by uremic toxins. Here, we studied in vitro and in vivo the effect of indoxyl sulfate (IS), an indolic uremic toxin, on myoblast proliferation, differentiation and expression of myogenic regulatory factors (MRF)—myoblast determination protein 1 (MyoD1), myogenin (Myog), Myogenic Factor 5 (Myf5) and myogenic regulatory factor 4 (Myf6/MRF4)—and expression of myosin heavy chain, Myh2.
Methods
C2C12 myoblasts were cultured in vitro and differentiated in myotubes for 7 days in the presence of IS at a uremic concentration of 200 µM. Myocytes morphology and differentiation was analyzed after hematoxylin-eosin staining. MRF genes’ expression was studied using reverse transcription polymerase chain reaction in myocytes and 5/6th nephrectomized mice muscle. Myf6/MRF4 protein expression was studied using enzyme-linked immunosorbent assay; MYH2 protein expression was studied using western blotting. The role of Aryl Hydrocarbon Receptor (AHR)—the cell receptor of IS—was studied by adding an AHR inhibitor into the cell culture milieu.
Results
In the presence of IS, the myotubes obtained were narrower and had fewer nuclei than control myotubes. The presence of IS during differentiation did not modify the gene expression of the MRFs Myf5, MyoD1 and Myog, but induced a decrease in expression of Myf6/MRF4 and MYH2 at the mRNA and the protein level. AHR inhibition by CH223191 did not reverse the decrease in Myf6/MRF4 mRNA expression induced by IS, which rules out the implication of the ARH genomic pathway. In 5/6th nephrectomized mice, the Myf6/MRF4 gene was down-regulated in striated muscles.
Conclusion
In conclusion, IS inhibits Myf6/MRF4 and MYH2 expression during differentiation of muscle cells, which could lead to a defect in myotube structure. Through these new mechanisms, IS could participate in muscle atrophy observed in CKD.</description><identifier>ISSN: 0931-0509</identifier><identifier>ISSN: 1460-2385</identifier><identifier>EISSN: 1460-2385</identifier><identifier>DOI: 10.1093/ndt/gfad123</identifier><identifier>PMID: 37349959</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Genetics ; Life Sciences</subject><ispartof>Nephrology, dialysis, transplantation, 2024-01, Vol.39 (1), p.103-113</ispartof><rights>The Author(s) 2023. Published by Oxford University Press on behalf of the ERA. 2023</rights><rights>The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c354t-ec71f4698179e83a6412b4605627bd28eeef872dd3f5ba855dc9e22e9c3be69a3</citedby><cites>FETCH-LOGICAL-c354t-ec71f4698179e83a6412b4605627bd28eeef872dd3f5ba855dc9e22e9c3be69a3</cites><orcidid>0000-0002-5076-2420 ; 0000-0001-8344-1300 ; 0000-0001-9541-1264 ; 0000-0003-3339-9858 ; 0000-0002-8403-8203 ; 0000-0003-2531-9416 ; 0000-0002-4594-4676</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,1584,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37349959$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://amu.hal.science/hal-04254193$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Bataille, Stanislas</creatorcontrib><creatorcontrib>McKay, Nathalie</creatorcontrib><creatorcontrib>Koppe, Laetitia</creatorcontrib><creatorcontrib>Beau, Alice</creatorcontrib><creatorcontrib>Benoit, Bérengère</creatorcontrib><creatorcontrib>Bartoli, Marc</creatorcontrib><creatorcontrib>Da Silva, Nathalie</creatorcontrib><creatorcontrib>Poitevin, Stéphane</creatorcontrib><creatorcontrib>Aniort, Julien</creatorcontrib><creatorcontrib>Chermiti, Rania</creatorcontrib><creatorcontrib>Burtey, Stéphane</creatorcontrib><creatorcontrib>Dou, Laetitia</creatorcontrib><title>Indoxyl sulfate inhibits muscle cell differentiation via Myf6/MRF4 and MYH2 downregulation</title><title>Nephrology, dialysis, transplantation</title><addtitle>Nephrol Dial Transplant</addtitle><description>ABSTRACT
Background
Chronic kidney disease (CKD) is associated with a significant decrease in muscle strength and mass, possibly related to muscle cell damage by uremic toxins. Here, we studied in vitro and in vivo the effect of indoxyl sulfate (IS), an indolic uremic toxin, on myoblast proliferation, differentiation and expression of myogenic regulatory factors (MRF)—myoblast determination protein 1 (MyoD1), myogenin (Myog), Myogenic Factor 5 (Myf5) and myogenic regulatory factor 4 (Myf6/MRF4)—and expression of myosin heavy chain, Myh2.
Methods
C2C12 myoblasts were cultured in vitro and differentiated in myotubes for 7 days in the presence of IS at a uremic concentration of 200 µM. Myocytes morphology and differentiation was analyzed after hematoxylin-eosin staining. MRF genes’ expression was studied using reverse transcription polymerase chain reaction in myocytes and 5/6th nephrectomized mice muscle. Myf6/MRF4 protein expression was studied using enzyme-linked immunosorbent assay; MYH2 protein expression was studied using western blotting. The role of Aryl Hydrocarbon Receptor (AHR)—the cell receptor of IS—was studied by adding an AHR inhibitor into the cell culture milieu.
Results
In the presence of IS, the myotubes obtained were narrower and had fewer nuclei than control myotubes. The presence of IS during differentiation did not modify the gene expression of the MRFs Myf5, MyoD1 and Myog, but induced a decrease in expression of Myf6/MRF4 and MYH2 at the mRNA and the protein level. AHR inhibition by CH223191 did not reverse the decrease in Myf6/MRF4 mRNA expression induced by IS, which rules out the implication of the ARH genomic pathway. In 5/6th nephrectomized mice, the Myf6/MRF4 gene was down-regulated in striated muscles.
Conclusion
In conclusion, IS inhibits Myf6/MRF4 and MYH2 expression during differentiation of muscle cells, which could lead to a defect in myotube structure. Through these new mechanisms, IS could participate in muscle atrophy observed in CKD.</description><subject>Genetics</subject><subject>Life Sciences</subject><issn>0931-0509</issn><issn>1460-2385</issn><issn>1460-2385</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp90E1Lw0AQBuBFFFurJ--yJ1Ekdj-T7LEUtUKLIHrQy7LJztqVNKnZRO2_N7W1R08DMw8vzIvQKSXXlCg-LG0zfHPGUsb3UJ-KmESMp3If9bsrjYgkqoeOQngnhCiWJIeoxxMulJKqj17vS1t9rwoc2sKZBrAv5z7zTcCLNuQF4ByKAlvvHNRQNt40virxpzd4tnLxcPZ4K7ApLZ69TBi21VdZw1tb_KpjdOBMEeBkOwfo-fbmaTyJpg939-PRNMq5FE0EeUKdiFVKEwUpN7GgLOuekDFLMstSAHBpwqzlTmYmldLmChgDlfMMYmX4AF1ucuem0MvaL0y90pXxejKa6vWOCCYFVfyTdvZiY5d19dFCaPTCh_WLpoSqDZqlTAlOCWcdvdrQvK5CqMHtsinR6-J1V7zeFt_ps21wmy3A7uxf0x0434CqXf6b9ANjNou3</recordid><startdate>20240101</startdate><enddate>20240101</enddate><creator>Bataille, Stanislas</creator><creator>McKay, Nathalie</creator><creator>Koppe, Laetitia</creator><creator>Beau, Alice</creator><creator>Benoit, Bérengère</creator><creator>Bartoli, Marc</creator><creator>Da Silva, Nathalie</creator><creator>Poitevin, Stéphane</creator><creator>Aniort, Julien</creator><creator>Chermiti, Rania</creator><creator>Burtey, Stéphane</creator><creator>Dou, Laetitia</creator><general>Oxford University Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><orcidid>https://orcid.org/0000-0002-5076-2420</orcidid><orcidid>https://orcid.org/0000-0001-8344-1300</orcidid><orcidid>https://orcid.org/0000-0001-9541-1264</orcidid><orcidid>https://orcid.org/0000-0003-3339-9858</orcidid><orcidid>https://orcid.org/0000-0002-8403-8203</orcidid><orcidid>https://orcid.org/0000-0003-2531-9416</orcidid><orcidid>https://orcid.org/0000-0002-4594-4676</orcidid></search><sort><creationdate>20240101</creationdate><title>Indoxyl sulfate inhibits muscle cell differentiation via Myf6/MRF4 and MYH2 downregulation</title><author>Bataille, Stanislas ; McKay, Nathalie ; Koppe, Laetitia ; Beau, Alice ; Benoit, Bérengère ; Bartoli, Marc ; Da Silva, Nathalie ; Poitevin, Stéphane ; Aniort, Julien ; Chermiti, Rania ; Burtey, Stéphane ; Dou, Laetitia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c354t-ec71f4698179e83a6412b4605627bd28eeef872dd3f5ba855dc9e22e9c3be69a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Genetics</topic><topic>Life Sciences</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bataille, Stanislas</creatorcontrib><creatorcontrib>McKay, Nathalie</creatorcontrib><creatorcontrib>Koppe, Laetitia</creatorcontrib><creatorcontrib>Beau, Alice</creatorcontrib><creatorcontrib>Benoit, Bérengère</creatorcontrib><creatorcontrib>Bartoli, Marc</creatorcontrib><creatorcontrib>Da Silva, Nathalie</creatorcontrib><creatorcontrib>Poitevin, Stéphane</creatorcontrib><creatorcontrib>Aniort, Julien</creatorcontrib><creatorcontrib>Chermiti, Rania</creatorcontrib><creatorcontrib>Burtey, Stéphane</creatorcontrib><creatorcontrib>Dou, Laetitia</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><jtitle>Nephrology, dialysis, transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bataille, Stanislas</au><au>McKay, Nathalie</au><au>Koppe, Laetitia</au><au>Beau, Alice</au><au>Benoit, Bérengère</au><au>Bartoli, Marc</au><au>Da Silva, Nathalie</au><au>Poitevin, Stéphane</au><au>Aniort, Julien</au><au>Chermiti, Rania</au><au>Burtey, Stéphane</au><au>Dou, Laetitia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Indoxyl sulfate inhibits muscle cell differentiation via Myf6/MRF4 and MYH2 downregulation</atitle><jtitle>Nephrology, dialysis, transplantation</jtitle><addtitle>Nephrol Dial Transplant</addtitle><date>2024-01-01</date><risdate>2024</risdate><volume>39</volume><issue>1</issue><spage>103</spage><epage>113</epage><pages>103-113</pages><issn>0931-0509</issn><issn>1460-2385</issn><eissn>1460-2385</eissn><abstract>ABSTRACT
Background
Chronic kidney disease (CKD) is associated with a significant decrease in muscle strength and mass, possibly related to muscle cell damage by uremic toxins. Here, we studied in vitro and in vivo the effect of indoxyl sulfate (IS), an indolic uremic toxin, on myoblast proliferation, differentiation and expression of myogenic regulatory factors (MRF)—myoblast determination protein 1 (MyoD1), myogenin (Myog), Myogenic Factor 5 (Myf5) and myogenic regulatory factor 4 (Myf6/MRF4)—and expression of myosin heavy chain, Myh2.
Methods
C2C12 myoblasts were cultured in vitro and differentiated in myotubes for 7 days in the presence of IS at a uremic concentration of 200 µM. Myocytes morphology and differentiation was analyzed after hematoxylin-eosin staining. MRF genes’ expression was studied using reverse transcription polymerase chain reaction in myocytes and 5/6th nephrectomized mice muscle. Myf6/MRF4 protein expression was studied using enzyme-linked immunosorbent assay; MYH2 protein expression was studied using western blotting. The role of Aryl Hydrocarbon Receptor (AHR)—the cell receptor of IS—was studied by adding an AHR inhibitor into the cell culture milieu.
Results
In the presence of IS, the myotubes obtained were narrower and had fewer nuclei than control myotubes. The presence of IS during differentiation did not modify the gene expression of the MRFs Myf5, MyoD1 and Myog, but induced a decrease in expression of Myf6/MRF4 and MYH2 at the mRNA and the protein level. AHR inhibition by CH223191 did not reverse the decrease in Myf6/MRF4 mRNA expression induced by IS, which rules out the implication of the ARH genomic pathway. In 5/6th nephrectomized mice, the Myf6/MRF4 gene was down-regulated in striated muscles.
Conclusion
In conclusion, IS inhibits Myf6/MRF4 and MYH2 expression during differentiation of muscle cells, which could lead to a defect in myotube structure. Through these new mechanisms, IS could participate in muscle atrophy observed in CKD.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>37349959</pmid><doi>10.1093/ndt/gfad123</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-5076-2420</orcidid><orcidid>https://orcid.org/0000-0001-8344-1300</orcidid><orcidid>https://orcid.org/0000-0001-9541-1264</orcidid><orcidid>https://orcid.org/0000-0003-3339-9858</orcidid><orcidid>https://orcid.org/0000-0002-8403-8203</orcidid><orcidid>https://orcid.org/0000-0003-2531-9416</orcidid><orcidid>https://orcid.org/0000-0002-4594-4676</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current) |
| subjects | Genetics Life Sciences |
| title | Indoxyl sulfate inhibits muscle cell differentiation via Myf6/MRF4 and MYH2 downregulation |
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