Evaluation of functional erythropoietin receptor status in skeletal muscle in vivo: acute and prolonged studies in healthy human subjects
Erythropoietin receptors have been identified in human skeletal muscle tissue, but downstream signal transduction has not been investigated. We therefore studied in vivo effects of systemic erythropoietin exposure in human skeletal muscle. The protocols involved 1) acute effects of a single bolus in...
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| Veröffentlicht in: | PloS one 2012-02, Vol.7 (2), p.e31857 |
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| creator | Christensen, Britt Lundby, Carsten Jessen, Niels Nielsen, Thomas S Vestergaard, Poul F Møller, Niels Pilegaard, Henriette Pedersen, Steen B Kopchick, John J Jørgensen, Jens Otto L |
| description | Erythropoietin receptors have been identified in human skeletal muscle tissue, but downstream signal transduction has not been investigated. We therefore studied in vivo effects of systemic erythropoietin exposure in human skeletal muscle.
The protocols involved 1) acute effects of a single bolus injection of erythropoietin followed by consecutive muscle biopsies for 1-10 hours, and 2) a separate study with prolonged administration for 16 days with biopsies obtained before and after. The presence of erythropoietin receptors in muscle tissue as well as activation of Epo signalling pathways (STAT5, MAPK, Akt, IKK) were analysed by western blotting. Changes in muscle protein profiles after prolonged erythropoietin treatment were evaluated by 2D gel-electrophoresis and mass spectrometry. The presence of the erythropoietin receptor in skeletal muscle was confirmed, by the M20 but not the C20 antibody. However, no significant changes in phosphorylation of the Epo-R, STAT5, MAPK, Akt, Lyn, IKK, and p70S6K after erythropoietin administration were detected. The level of 8 protein spots were significantly altered after 16 days of rHuEpo treatment; one isoform of myosin light chain 3 and one of desmin/actin were decreased, while three isoforms of creatine kinase and two of glyceraldehyd-3-phosphate dehydrogenase were increased.
Acute exposure to recombinant human erythropoietin is not associated by detectable activation of the Epo-R or downstream signalling targets in human skeletal muscle in the resting situation, whereas more prolonged exposure induces significant changes in the skeletal muscle proteome. The absence of functional Epo receptor activity in human skeletal muscle indicates that the long-term effects are indirect and probably related to an increased oxidative capacity in this tissue. |
| doi_str_mv | 10.1371/journal.pone.0031857 |
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The protocols involved 1) acute effects of a single bolus injection of erythropoietin followed by consecutive muscle biopsies for 1-10 hours, and 2) a separate study with prolonged administration for 16 days with biopsies obtained before and after. The presence of erythropoietin receptors in muscle tissue as well as activation of Epo signalling pathways (STAT5, MAPK, Akt, IKK) were analysed by western blotting. Changes in muscle protein profiles after prolonged erythropoietin treatment were evaluated by 2D gel-electrophoresis and mass spectrometry. The presence of the erythropoietin receptor in skeletal muscle was confirmed, by the M20 but not the C20 antibody. However, no significant changes in phosphorylation of the Epo-R, STAT5, MAPK, Akt, Lyn, IKK, and p70S6K after erythropoietin administration were detected. The level of 8 protein spots were significantly altered after 16 days of rHuEpo treatment; one isoform of myosin light chain 3 and one of desmin/actin were decreased, while three isoforms of creatine kinase and two of glyceraldehyd-3-phosphate dehydrogenase were increased.
Acute exposure to recombinant human erythropoietin is not associated by detectable activation of the Epo-R or downstream signalling targets in human skeletal muscle in the resting situation, whereas more prolonged exposure induces significant changes in the skeletal muscle proteome. The absence of functional Epo receptor activity in human skeletal muscle indicates that the long-term effects are indirect and probably related to an increased oxidative capacity in this tissue.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0031857</identifier><identifier>PMID: 22384088</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Actin ; Acute effects ; Adult ; AKT protein ; Analysis ; Biology ; Biopsy - methods ; Breast cancer ; Cellular signal transduction ; Creatine ; Creatine kinase ; Desmin ; Drug delivery systems ; Drug dosages ; Electrophoresis, Gel, Two-Dimensional - methods ; Endocrinology ; Erythropoietin ; Erythropoietin - metabolism ; Erythropoietin receptors ; Ethics ; Exposure ; Hospitals ; Humans ; Hypoxia ; In vivo methods and tests ; Internal medicine ; Isoforms ; Kinases ; Laboratories ; Long-term effects ; Male ; MAP kinase ; Mass spectrometry ; Mass Spectrometry - methods ; Mass spectroscopy ; Medical research ; Medicine ; Muscle proteins ; Muscle, Skeletal - metabolism ; Muscles ; Musculoskeletal system ; Myosin ; Oxidation ; Oxygen - metabolism ; Phosphates ; Phosphorylation ; Physiology ; Polymerase Chain Reaction - methods ; Protein Isoforms ; Proteins ; Proteomes ; Proteomics - methods ; Receptors ; Receptors, Erythropoietin - metabolism ; Receptors, Erythropoietin - physiology ; Recombinant Proteins - metabolism ; RNA, Messenger - metabolism ; Rodents ; Signal Transduction ; Signaling ; Skeletal muscle ; Stat5 protein ; Studies ; Time Factors ; Transduction ; Western blotting</subject><ispartof>PloS one, 2012-02, Vol.7 (2), p.e31857</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Christensen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Christensen et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c659t-93a5d9e870e37046e6dce31e5fedf9152fa7ecb3892c92411de322f580a9c7a43</citedby><cites>FETCH-LOGICAL-c659t-93a5d9e870e37046e6dce31e5fedf9152fa7ecb3892c92411de322f580a9c7a43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285196/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285196/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22384088$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Lucia, Alejandro</contributor><creatorcontrib>Christensen, Britt</creatorcontrib><creatorcontrib>Lundby, Carsten</creatorcontrib><creatorcontrib>Jessen, Niels</creatorcontrib><creatorcontrib>Nielsen, Thomas S</creatorcontrib><creatorcontrib>Vestergaard, Poul F</creatorcontrib><creatorcontrib>Møller, Niels</creatorcontrib><creatorcontrib>Pilegaard, Henriette</creatorcontrib><creatorcontrib>Pedersen, Steen B</creatorcontrib><creatorcontrib>Kopchick, John J</creatorcontrib><creatorcontrib>Jørgensen, Jens Otto L</creatorcontrib><title>Evaluation of functional erythropoietin receptor status in skeletal muscle in vivo: acute and prolonged studies in healthy human subjects</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Erythropoietin receptors have been identified in human skeletal muscle tissue, but downstream signal transduction has not been investigated. We therefore studied in vivo effects of systemic erythropoietin exposure in human skeletal muscle.
The protocols involved 1) acute effects of a single bolus injection of erythropoietin followed by consecutive muscle biopsies for 1-10 hours, and 2) a separate study with prolonged administration for 16 days with biopsies obtained before and after. The presence of erythropoietin receptors in muscle tissue as well as activation of Epo signalling pathways (STAT5, MAPK, Akt, IKK) were analysed by western blotting. Changes in muscle protein profiles after prolonged erythropoietin treatment were evaluated by 2D gel-electrophoresis and mass spectrometry. The presence of the erythropoietin receptor in skeletal muscle was confirmed, by the M20 but not the C20 antibody. However, no significant changes in phosphorylation of the Epo-R, STAT5, MAPK, Akt, Lyn, IKK, and p70S6K after erythropoietin administration were detected. The level of 8 protein spots were significantly altered after 16 days of rHuEpo treatment; one isoform of myosin light chain 3 and one of desmin/actin were decreased, while three isoforms of creatine kinase and two of glyceraldehyd-3-phosphate dehydrogenase were increased.
Acute exposure to recombinant human erythropoietin is not associated by detectable activation of the Epo-R or downstream signalling targets in human skeletal muscle in the resting situation, whereas more prolonged exposure induces significant changes in the skeletal muscle proteome. The absence of functional Epo receptor activity in human skeletal muscle indicates that the long-term effects are indirect and probably related to an increased oxidative capacity in this tissue.</description><subject>Actin</subject><subject>Acute effects</subject><subject>Adult</subject><subject>AKT protein</subject><subject>Analysis</subject><subject>Biology</subject><subject>Biopsy - methods</subject><subject>Breast cancer</subject><subject>Cellular signal transduction</subject><subject>Creatine</subject><subject>Creatine kinase</subject><subject>Desmin</subject><subject>Drug delivery systems</subject><subject>Drug dosages</subject><subject>Electrophoresis, Gel, Two-Dimensional - methods</subject><subject>Endocrinology</subject><subject>Erythropoietin</subject><subject>Erythropoietin - metabolism</subject><subject>Erythropoietin receptors</subject><subject>Ethics</subject><subject>Exposure</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>In vivo methods and tests</subject><subject>Internal medicine</subject><subject>Isoforms</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Long-term effects</subject><subject>Male</subject><subject>MAP kinase</subject><subject>Mass spectrometry</subject><subject>Mass Spectrometry - methods</subject><subject>Mass spectroscopy</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Muscle proteins</subject><subject>Muscle, Skeletal - metabolism</subject><subject>Muscles</subject><subject>Musculoskeletal system</subject><subject>Myosin</subject><subject>Oxidation</subject><subject>Oxygen - metabolism</subject><subject>Phosphates</subject><subject>Phosphorylation</subject><subject>Physiology</subject><subject>Polymerase Chain Reaction - methods</subject><subject>Protein Isoforms</subject><subject>Proteins</subject><subject>Proteomes</subject><subject>Proteomics - methods</subject><subject>Receptors</subject><subject>Receptors, Erythropoietin - metabolism</subject><subject>Receptors, Erythropoietin - physiology</subject><subject>Recombinant Proteins - metabolism</subject><subject>RNA, Messenger - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Skeletal muscle</subject><subject>Stat5 protein</subject><subject>Studies</subject><subject>Time Factors</subject><subject>Transduction</subject><subject>Western 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one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Christensen, Britt</au><au>Lundby, Carsten</au><au>Jessen, Niels</au><au>Nielsen, Thomas S</au><au>Vestergaard, Poul F</au><au>Møller, Niels</au><au>Pilegaard, Henriette</au><au>Pedersen, Steen B</au><au>Kopchick, John J</au><au>Jørgensen, Jens Otto L</au><au>Lucia, Alejandro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of functional erythropoietin receptor status in skeletal muscle in vivo: acute and prolonged studies in healthy human subjects</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-02-22</date><risdate>2012</risdate><volume>7</volume><issue>2</issue><spage>e31857</spage><pages>e31857-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Erythropoietin receptors have been identified in human skeletal muscle tissue, but downstream signal transduction has not been investigated. We therefore studied in vivo effects of systemic erythropoietin exposure in human skeletal muscle.
The protocols involved 1) acute effects of a single bolus injection of erythropoietin followed by consecutive muscle biopsies for 1-10 hours, and 2) a separate study with prolonged administration for 16 days with biopsies obtained before and after. The presence of erythropoietin receptors in muscle tissue as well as activation of Epo signalling pathways (STAT5, MAPK, Akt, IKK) were analysed by western blotting. Changes in muscle protein profiles after prolonged erythropoietin treatment were evaluated by 2D gel-electrophoresis and mass spectrometry. The presence of the erythropoietin receptor in skeletal muscle was confirmed, by the M20 but not the C20 antibody. However, no significant changes in phosphorylation of the Epo-R, STAT5, MAPK, Akt, Lyn, IKK, and p70S6K after erythropoietin administration were detected. The level of 8 protein spots were significantly altered after 16 days of rHuEpo treatment; one isoform of myosin light chain 3 and one of desmin/actin were decreased, while three isoforms of creatine kinase and two of glyceraldehyd-3-phosphate dehydrogenase were increased.
Acute exposure to recombinant human erythropoietin is not associated by detectable activation of the Epo-R or downstream signalling targets in human skeletal muscle in the resting situation, whereas more prolonged exposure induces significant changes in the skeletal muscle proteome. The absence of functional Epo receptor activity in human skeletal muscle indicates that the long-term effects are indirect and probably related to an increased oxidative capacity in this tissue.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22384088</pmid><doi>10.1371/journal.pone.0031857</doi><tpages>e31857</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-02, Vol.7 (2), p.e31857 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1323859350 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Actin Acute effects Adult AKT protein Analysis Biology Biopsy - methods Breast cancer Cellular signal transduction Creatine Creatine kinase Desmin Drug delivery systems Drug dosages Electrophoresis, Gel, Two-Dimensional - methods Endocrinology Erythropoietin Erythropoietin - metabolism Erythropoietin receptors Ethics Exposure Hospitals Humans Hypoxia In vivo methods and tests Internal medicine Isoforms Kinases Laboratories Long-term effects Male MAP kinase Mass spectrometry Mass Spectrometry - methods Mass spectroscopy Medical research Medicine Muscle proteins Muscle, Skeletal - metabolism Muscles Musculoskeletal system Myosin Oxidation Oxygen - metabolism Phosphates Phosphorylation Physiology Polymerase Chain Reaction - methods Protein Isoforms Proteins Proteomes Proteomics - methods Receptors Receptors, Erythropoietin - metabolism Receptors, Erythropoietin - physiology Recombinant Proteins - metabolism RNA, Messenger - metabolism Rodents Signal Transduction Signaling Skeletal muscle Stat5 protein Studies Time Factors Transduction Western blotting |
| title | Evaluation of functional erythropoietin receptor status in skeletal muscle in vivo: acute and prolonged studies in healthy human subjects |
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