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...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2021-09, Vol.118 (37), p.1-12 |
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| creator | Mathes, Sebastian Fahrner, Alexandra Ghoshdastider, Umesh Rüdiger, Hannes A. Leunig, Michael Wolfrum, Christian Krützfeldt, Jan |
| 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 |
| doi_str_mv | 10.1073/pnas.2021013118 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2021013118</identifier><identifier>PMID: 34493647</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adipocytes ; Adipogenesis ; Adipose tissue ; Adipose Tissue - metabolism ; Adipose Tissue - pathology ; Aged ; Bioaccumulation ; Biological Sciences ; Cell Differentiation ; Evolutionary conservation ; Fibroblast growth factor 2 ; Fibroblast Growth Factor 2 - genetics ; Fibroblast Growth Factor 2 - metabolism ; Fra1 protein ; Growth factors ; Humans ; MicroRNAs - genetics ; miRNA ; Muscle, Skeletal - metabolism ; Muscle, Skeletal - pathology ; Muscles ; Musculoskeletal system ; Osteonectin ; Osteonectin - genetics ; Osteonectin - metabolism ; Progenitor cells ; Proto-Oncogene Proteins c-fos - genetics ; Proto-Oncogene Proteins c-fos - metabolism ; Ribonucleic acid ; RNA ; Signal Transduction ; Signaling ; Skeletal muscle ; Transcription activation ; Transcription factors ; Viruses</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2021-09, Vol.118 (37), p.1-12</ispartof><rights>Copyright © 2021 the Author(s). Published by PNAS.</rights><rights>Copyright National Academy of Sciences Sep 14, 2021</rights><rights>Copyright © 2021 the Author(s). Published by PNAS. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-78315cadf2c46a34faf9ab10c70a7c966054f889ac6a6b4979aef46bf5211d6f3</citedby><cites>FETCH-LOGICAL-c509t-78315cadf2c46a34faf9ab10c70a7c966054f889ac6a6b4979aef46bf5211d6f3</cites><orcidid>0000-0001-7071-7128 ; 0000-0002-7967-0909 ; 0000-0003-1305-0982</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/27075763$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/27075763$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34493647$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mathes, Sebastian</creatorcontrib><creatorcontrib>Fahrner, Alexandra</creatorcontrib><creatorcontrib>Ghoshdastider, Umesh</creatorcontrib><creatorcontrib>Rüdiger, Hannes A.</creatorcontrib><creatorcontrib>Leunig, Michael</creatorcontrib><creatorcontrib>Wolfrum, Christian</creatorcontrib><creatorcontrib>Krützfeldt, Jan</creatorcontrib><title>FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><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.</description><subject>Adipocytes</subject><subject>Adipogenesis</subject><subject>Adipose tissue</subject><subject>Adipose Tissue - metabolism</subject><subject>Adipose Tissue - pathology</subject><subject>Aged</subject><subject>Bioaccumulation</subject><subject>Biological Sciences</subject><subject>Cell Differentiation</subject><subject>Evolutionary conservation</subject><subject>Fibroblast growth factor 2</subject><subject>Fibroblast Growth Factor 2 - genetics</subject><subject>Fibroblast Growth Factor 2 - metabolism</subject><subject>Fra1 protein</subject><subject>Growth factors</subject><subject>Humans</subject><subject>MicroRNAs - genetics</subject><subject>miRNA</subject><subject>Muscle, Skeletal - metabolism</subject><subject>Muscle, Skeletal - pathology</subject><subject>Muscles</subject><subject>Musculoskeletal system</subject><subject>Osteonectin</subject><subject>Osteonectin - genetics</subject><subject>Osteonectin - metabolism</subject><subject>Progenitor cells</subject><subject>Proto-Oncogene Proteins c-fos - genetics</subject><subject>Proto-Oncogene Proteins c-fos - metabolism</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Skeletal muscle</subject><subject>Transcription activation</subject><subject>Transcription factors</subject><subject>Viruses</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1v1DAQhi0EosvCmRMoEhcuaccfseMLUlWxBakSFzhbs46TeknsYCeVuPEf-If8EhK2LB-nkWaeeTXzvoQ8p3BOQfGLMWA-Z8AoUE5p_YBsKGhaSqHhIdkAMFXWgokz8iTnAwDoqobH5IwLobkUakO63fWuZD--fW_c6ELjwlRk3wXsfegKtJO_w8k1hQ8Fdku9nQcMRf7sejdhXwxztr0rxhSHOLm8YFPCtTn3mAps_Bg7F1z2-Sl51GKf3bP7uiWfdm8_Xr0rbz5cv7-6vCltBXoqVc1pZbFpmRUSuWix1binYBWgslpKqERb1xqtRLkXWml0rZD7tmKUNrLlW_LmqDvO-8E11q0X9WZMfsD01UT05t9J8Lemi3emXi1hsAi8vhdI8cvs8mQGn63rewwuztmwSgFXgi3ub8mr_9BDnNPi3S-K1xo08IW6OFI2xZyTa0_HUDBriGYN0fwJcdl4-fcPJ_53agvw4ggc8hTTac4UqEpJzn8CaEWlUg</recordid><startdate>20210914</startdate><enddate>20210914</enddate><creator>Mathes, Sebastian</creator><creator>Fahrner, Alexandra</creator><creator>Ghoshdastider, Umesh</creator><creator>Rüdiger, Hannes A.</creator><creator>Leunig, Michael</creator><creator>Wolfrum, Christian</creator><creator>Krützfeldt, Jan</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7071-7128</orcidid><orcidid>https://orcid.org/0000-0002-7967-0909</orcidid><orcidid>https://orcid.org/0000-0003-1305-0982</orcidid></search><sort><creationdate>20210914</creationdate><title>FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis</title><author>Mathes, Sebastian ; 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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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>34493647</pmid><doi>10.1073/pnas.2021013118</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-7071-7128</orcidid><orcidid>https://orcid.org/0000-0002-7967-0909</orcidid><orcidid>https://orcid.org/0000-0003-1305-0982</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adipocytes Adipogenesis Adipose tissue Adipose Tissue - metabolism Adipose Tissue - pathology Aged Bioaccumulation Biological Sciences Cell Differentiation Evolutionary conservation Fibroblast growth factor 2 Fibroblast Growth Factor 2 - genetics Fibroblast Growth Factor 2 - metabolism Fra1 protein Growth factors Humans MicroRNAs - genetics miRNA Muscle, Skeletal - metabolism Muscle, Skeletal - pathology Muscles Musculoskeletal system Osteonectin Osteonectin - genetics Osteonectin - metabolism Progenitor cells Proto-Oncogene Proteins c-fos - genetics Proto-Oncogene Proteins c-fos - metabolism Ribonucleic acid RNA Signal Transduction Signaling Skeletal muscle Transcription activation Transcription factors Viruses |
| title | FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis |
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