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GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting
Patients with end-stage liver disease exhibit progressive skeletal muscle atrophy, highlighting a negative crosstalk between the injured liver and muscle. Our study was to determine whether TGFβ ligands function as the mediators. Acute or chronic liver injury was induced by a single or repeated admi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10377408/ https://www.ncbi.nlm.nih.gov/pubmed/37509548 http://dx.doi.org/10.3390/biomedicines11071909 |
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author | Culver, Alexander Hamang, Matthew Wang, Yan Jiang, Huaizhou Yanum, Jennifer White, Emily Gawrieh, Samer Vuppalanchi, Raj K. Chalasani, Naga P. Dai, Guoli Yaden, Benjamin C. |
author_facet | Culver, Alexander Hamang, Matthew Wang, Yan Jiang, Huaizhou Yanum, Jennifer White, Emily Gawrieh, Samer Vuppalanchi, Raj K. Chalasani, Naga P. Dai, Guoli Yaden, Benjamin C. |
author_sort | Culver, Alexander |
collection | PubMed |
description | Patients with end-stage liver disease exhibit progressive skeletal muscle atrophy, highlighting a negative crosstalk between the injured liver and muscle. Our study was to determine whether TGFβ ligands function as the mediators. Acute or chronic liver injury was induced by a single or repeated administration of carbon tetrachloride. Skeletal muscle injury and repair was induced by intramuscular injection of cardiotoxin. Activin type IIB receptor (ActRIIB) ligands and growth differentiation factor 8 (Gdf8) were neutralized with ActRIIB-Fc fusion protein and a Gdf8-specific antibody, respectively. We found that acute hepatic injury induced rapid and adverse responses in muscle, which was blunted by neutralizing ActRIIB ligands. Chronic liver injury caused muscle atrophy and repair defects, which were prevented or reversed by inactivating ActRIIB ligands. Furthermore, we found that pericentral hepatocytes produce excessive Gdf8 in injured mouse liver and cirrhotic human liver. Specific inactivation of Gdf8 prevented liver injury-induced muscle atrophy, similar to neutralization of ActRIIB ligands. Inhibition of Gdf8 also reversed muscle atrophy in a treatment paradigm following chronic liver injury. Direct injection of exogenous Gdf8 protein into muscle along with acute focal muscle injury recapitulated similar dysregulated muscle regeneration as that observed with liver injury. The results indicate that injured liver negatively communicate with the muscle largely via Gdf8. Unexpectedly, inactivation of Gdf8 simultaneously ameliorated liver fibrosis in mice following chronic liver injury. In vitro, Gdf8 induced human hepatic stellate (LX-2) cells to form a septa-like structure and stimulated expression of profibrotic factors. Our findings identified Gdf8 as a novel hepatomyokine contributing to injured liver–muscle negative crosstalk along with liver injury progression. |
format | Online Article Text |
id | pubmed-10377408 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-103774082023-07-29 GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting Culver, Alexander Hamang, Matthew Wang, Yan Jiang, Huaizhou Yanum, Jennifer White, Emily Gawrieh, Samer Vuppalanchi, Raj K. Chalasani, Naga P. Dai, Guoli Yaden, Benjamin C. Biomedicines Article Patients with end-stage liver disease exhibit progressive skeletal muscle atrophy, highlighting a negative crosstalk between the injured liver and muscle. Our study was to determine whether TGFβ ligands function as the mediators. Acute or chronic liver injury was induced by a single or repeated administration of carbon tetrachloride. Skeletal muscle injury and repair was induced by intramuscular injection of cardiotoxin. Activin type IIB receptor (ActRIIB) ligands and growth differentiation factor 8 (Gdf8) were neutralized with ActRIIB-Fc fusion protein and a Gdf8-specific antibody, respectively. We found that acute hepatic injury induced rapid and adverse responses in muscle, which was blunted by neutralizing ActRIIB ligands. Chronic liver injury caused muscle atrophy and repair defects, which were prevented or reversed by inactivating ActRIIB ligands. Furthermore, we found that pericentral hepatocytes produce excessive Gdf8 in injured mouse liver and cirrhotic human liver. Specific inactivation of Gdf8 prevented liver injury-induced muscle atrophy, similar to neutralization of ActRIIB ligands. Inhibition of Gdf8 also reversed muscle atrophy in a treatment paradigm following chronic liver injury. Direct injection of exogenous Gdf8 protein into muscle along with acute focal muscle injury recapitulated similar dysregulated muscle regeneration as that observed with liver injury. The results indicate that injured liver negatively communicate with the muscle largely via Gdf8. Unexpectedly, inactivation of Gdf8 simultaneously ameliorated liver fibrosis in mice following chronic liver injury. In vitro, Gdf8 induced human hepatic stellate (LX-2) cells to form a septa-like structure and stimulated expression of profibrotic factors. Our findings identified Gdf8 as a novel hepatomyokine contributing to injured liver–muscle negative crosstalk along with liver injury progression. MDPI 2023-07-06 /pmc/articles/PMC10377408/ /pubmed/37509548 http://dx.doi.org/10.3390/biomedicines11071909 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Culver, Alexander Hamang, Matthew Wang, Yan Jiang, Huaizhou Yanum, Jennifer White, Emily Gawrieh, Samer Vuppalanchi, Raj K. Chalasani, Naga P. Dai, Guoli Yaden, Benjamin C. GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting |
title | GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting |
title_full | GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting |
title_fullStr | GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting |
title_full_unstemmed | GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting |
title_short | GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting |
title_sort | gdf8 contributes to liver fibrogenesis and concomitant skeletal muscle wasting |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10377408/ https://www.ncbi.nlm.nih.gov/pubmed/37509548 http://dx.doi.org/10.3390/biomedicines11071909 |
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