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FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis
Aged skeletal muscle is markedly affected by fatty muscle infiltration, and strategies to reduce the occurrence of intramuscular adipocytes are urgently needed. Here, we show that fibroblast growth factor-2 (FGF-2) not only stimulates muscle growth but also promotes intramuscular adipogenesis. Using...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449320/ https://www.ncbi.nlm.nih.gov/pubmed/34493647 http://dx.doi.org/10.1073/pnas.2021013118 |
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author | Mathes, Sebastian Fahrner, Alexandra Ghoshdastider, Umesh Rüdiger, Hannes A. Leunig, Michael Wolfrum, Christian Krützfeldt, Jan |
author_facet | Mathes, Sebastian Fahrner, Alexandra Ghoshdastider, Umesh Rüdiger, Hannes A. Leunig, Michael Wolfrum, Christian Krützfeldt, Jan |
author_sort | Mathes, Sebastian |
collection | PubMed |
description | Aged skeletal muscle is markedly affected by fatty muscle infiltration, and strategies to reduce the occurrence of intramuscular adipocytes are urgently needed. Here, we show that fibroblast growth factor-2 (FGF-2) not only stimulates muscle growth but also promotes intramuscular adipogenesis. Using multiple screening assays upstream and downstream of microRNA (miR)-29a signaling, we located the secreted protein and adipogenic inhibitor SPARC to an FGF-2 signaling pathway that is conserved between skeletal muscle cells from mice and humans and that is activated in skeletal muscle of aged mice and humans. FGF-2 induces the miR-29a/SPARC axis through transcriptional activation of FRA-1, which binds and activates an evolutionary conserved AP-1 site element proximal in the miR-29a promoter. Genetic deletions in muscle cells and adeno-associated virus–mediated overexpression of FGF-2 or SPARC in mouse skeletal muscle revealed that this axis regulates differentiation of fibro/adipogenic progenitors in vitro and intramuscular adipose tissue (IMAT) formation in vivo. Skeletal muscle from human donors aged >75 y versus <55 y showed activation of FGF-2–dependent signaling and increased IMAT. Thus, our data highlights a disparate role of FGF-2 in adult skeletal muscle and reveals a pathway to combat fat accumulation in aged human skeletal muscle. |
format | Online Article Text |
id | pubmed-8449320 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-84493202021-10-04 FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis Mathes, Sebastian Fahrner, Alexandra Ghoshdastider, Umesh Rüdiger, Hannes A. Leunig, Michael Wolfrum, Christian Krützfeldt, Jan Proc Natl Acad Sci U S A Biological Sciences Aged skeletal muscle is markedly affected by fatty muscle infiltration, and strategies to reduce the occurrence of intramuscular adipocytes are urgently needed. Here, we show that fibroblast growth factor-2 (FGF-2) not only stimulates muscle growth but also promotes intramuscular adipogenesis. Using multiple screening assays upstream and downstream of microRNA (miR)-29a signaling, we located the secreted protein and adipogenic inhibitor SPARC to an FGF-2 signaling pathway that is conserved between skeletal muscle cells from mice and humans and that is activated in skeletal muscle of aged mice and humans. FGF-2 induces the miR-29a/SPARC axis through transcriptional activation of FRA-1, which binds and activates an evolutionary conserved AP-1 site element proximal in the miR-29a promoter. Genetic deletions in muscle cells and adeno-associated virus–mediated overexpression of FGF-2 or SPARC in mouse skeletal muscle revealed that this axis regulates differentiation of fibro/adipogenic progenitors in vitro and intramuscular adipose tissue (IMAT) formation in vivo. Skeletal muscle from human donors aged >75 y versus <55 y showed activation of FGF-2–dependent signaling and increased IMAT. Thus, our data highlights a disparate role of FGF-2 in adult skeletal muscle and reveals a pathway to combat fat accumulation in aged human skeletal muscle. National Academy of Sciences 2021-09-14 2021-09-07 /pmc/articles/PMC8449320/ /pubmed/34493647 http://dx.doi.org/10.1073/pnas.2021013118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Mathes, Sebastian Fahrner, Alexandra Ghoshdastider, Umesh Rüdiger, Hannes A. Leunig, Michael Wolfrum, Christian Krützfeldt, Jan FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis |
title | FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis |
title_full | FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis |
title_fullStr | FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis |
title_full_unstemmed | FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis |
title_short | FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis |
title_sort | fgf-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449320/ https://www.ncbi.nlm.nih.gov/pubmed/34493647 http://dx.doi.org/10.1073/pnas.2021013118 |
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