Activated protein synthesis and suppressed protein breakdown signaling in skeletal muscle of critically ill patients
Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β) and forkhead box O (FoxO) pathways, but it is unknown how these pathways are regulated in critically ill human muscle. To describe factors involved...
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| Veröffentlicht in: | PloS one 2011-03, Vol.6 (3), p.e18090-e18090 |
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| creator | Jespersen, Jakob G Nedergaard, Anders Reitelseder, Søren Mikkelsen, Ulla R Dideriksen, Kasper J Agergaard, Jakob Kreiner, Frederik Pott, Frank C Schjerling, Peter Kjaer, Michael |
| description | Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β) and forkhead box O (FoxO) pathways, but it is unknown how these pathways are regulated in critically ill human muscle. To describe factors involved in muscle mass regulation, we investigated the phosphorylation and expression of key factors in these protein synthesis and breakdown signaling pathways in thigh skeletal muscle of critically ill intensive care unit (ICU) patients compared with healthy controls.
ICU patients were systemically inflamed, moderately hyperglycemic, received insulin therapy, and showed a tendency to lower plasma branched chain amino acids compared with controls. Using Western blotting we measured Akt, GSK3β, mTOR, ribosomal protein S6 kinase (S6k), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), and muscle ring finger protein 1 (MuRF1); and by RT-PCR we determined mRNA expression of, among others, insulin-like growth factor 1 (IGF-1), FoxO 1, 3 and 4, atrogin1, MuRF1, interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and myostatin. Unexpectedly, in critically ill ICU patients Akt-mTOR-S6k signaling was substantially higher compared with controls. FoxO1 mRNA was higher in patients, whereas FoxO3, atrogin1 and myostatin mRNAs and MuRF1 protein were lower compared with controls. A moderate correlation (r2=0.36, p |
| doi_str_mv | 10.1371/journal.pone.0018090 |
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ICU patients were systemically inflamed, moderately hyperglycemic, received insulin therapy, and showed a tendency to lower plasma branched chain amino acids compared with controls. Using Western blotting we measured Akt, GSK3β, mTOR, ribosomal protein S6 kinase (S6k), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), and muscle ring finger protein 1 (MuRF1); and by RT-PCR we determined mRNA expression of, among others, insulin-like growth factor 1 (IGF-1), FoxO 1, 3 and 4, atrogin1, MuRF1, interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and myostatin. Unexpectedly, in critically ill ICU patients Akt-mTOR-S6k signaling was substantially higher compared with controls. FoxO1 mRNA was higher in patients, whereas FoxO3, atrogin1 and myostatin mRNAs and MuRF1 protein were lower compared with controls. A moderate correlation (r2=0.36, p<0.05) between insulin infusion dose and phosphorylated Akt was demonstrated.
We present for the first time muscle protein turnover signaling in critically ill ICU patients, and we show signaling pathway activity towards a stimulation of muscle protein synthesis and a somewhat inhibited proteolysis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0018090</identifier><identifier>PMID: 21483870</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Aged ; Aging ; AKT protein ; Alcohol ; Amino acids ; Biology ; Blotting, Western ; Bone surgery ; Branched chain amino acids ; Breakdown ; Care and treatment ; Case-Control Studies ; Cell cycle ; Chain branching ; Comparative analysis ; Critical Illness ; Diabetes ; Diabetes therapy ; Dietary fiber ; Electrolytes ; Female ; Forkhead protein ; FOXO1 protein ; FOXO3 protein ; Gene expression ; Glucose ; Glycogen ; Glycogen synthase kinase 3 ; Glycogen synthesis ; Hospital patients ; Hospitals ; Humans ; Illnesses ; Inflammation ; Insulin ; Insulin-like growth factor I ; Insulin-like growth factors ; Interleukin ; Interleukin 6 ; Interleukins ; Kinases ; Male ; Medicine ; Metabolism ; Middle Aged ; Mortality ; Muscle Proteins - genetics ; Muscle Proteins - metabolism ; Muscle, Skeletal - metabolism ; Muscles ; Musculoskeletal system ; Myostatin ; Orthopedics ; Pathways ; Patients ; Phosphates ; Phosphorylation ; Polymerase chain reaction ; Protein binding ; Protein Biosynthesis ; Protein synthesis ; Protein turnover ; Proteins ; Proteolysis ; Rapamycin ; Reverse Transcriptase Polymerase Chain Reaction ; Ribosomal protein S6 ; Ribosomal protein S6 kinase ; RNA ; Rodents ; Sepsis ; Signal transduction ; Signal Transduction - genetics ; Signal Transduction - physiology ; Signaling ; Skeletal muscle ; Thigh ; TOR protein ; Translation (Genetics) ; Type 2 diabetes ; Western blotting</subject><ispartof>PloS one, 2011-03, Vol.6 (3), p.e18090-e18090</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Jespersen 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>Jespersen et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-f656fe82b82429da7344fb8ce8abf5b269fd8824c0f4c1c8a7a51b539eb498273</citedby><cites>FETCH-LOGICAL-c691t-f656fe82b82429da7344fb8ce8abf5b269fd8824c0f4c1c8a7a51b539eb498273</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/PMC3069050/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069050/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21483870$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Agarwal, Sudha</contributor><creatorcontrib>Jespersen, Jakob G</creatorcontrib><creatorcontrib>Nedergaard, Anders</creatorcontrib><creatorcontrib>Reitelseder, Søren</creatorcontrib><creatorcontrib>Mikkelsen, Ulla R</creatorcontrib><creatorcontrib>Dideriksen, Kasper J</creatorcontrib><creatorcontrib>Agergaard, Jakob</creatorcontrib><creatorcontrib>Kreiner, Frederik</creatorcontrib><creatorcontrib>Pott, Frank C</creatorcontrib><creatorcontrib>Schjerling, Peter</creatorcontrib><creatorcontrib>Kjaer, Michael</creatorcontrib><title>Activated protein synthesis and suppressed protein breakdown signaling in skeletal muscle of critically ill patients</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β) and forkhead box O (FoxO) pathways, but it is unknown how these pathways are regulated in critically ill human muscle. To describe factors involved in muscle mass regulation, we investigated the phosphorylation and expression of key factors in these protein synthesis and breakdown signaling pathways in thigh skeletal muscle of critically ill intensive care unit (ICU) patients compared with healthy controls.
ICU patients were systemically inflamed, moderately hyperglycemic, received insulin therapy, and showed a tendency to lower plasma branched chain amino acids compared with controls. Using Western blotting we measured Akt, GSK3β, mTOR, ribosomal protein S6 kinase (S6k), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), and muscle ring finger protein 1 (MuRF1); and by RT-PCR we determined mRNA expression of, among others, insulin-like growth factor 1 (IGF-1), FoxO 1, 3 and 4, atrogin1, MuRF1, interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and myostatin. Unexpectedly, in critically ill ICU patients Akt-mTOR-S6k signaling was substantially higher compared with controls. FoxO1 mRNA was higher in patients, whereas FoxO3, atrogin1 and myostatin mRNAs and MuRF1 protein were lower compared with controls. A moderate correlation (r2=0.36, p<0.05) between insulin infusion dose and phosphorylated Akt was demonstrated.
We present for the first time muscle protein turnover signaling in critically ill ICU patients, and we show signaling pathway activity towards a stimulation of muscle protein synthesis and a somewhat inhibited proteolysis.</description><subject>Adult</subject><subject>Aged</subject><subject>Aging</subject><subject>AKT protein</subject><subject>Alcohol</subject><subject>Amino acids</subject><subject>Biology</subject><subject>Blotting, Western</subject><subject>Bone surgery</subject><subject>Branched chain amino acids</subject><subject>Breakdown</subject><subject>Care and treatment</subject><subject>Case-Control Studies</subject><subject>Cell cycle</subject><subject>Chain branching</subject><subject>Comparative analysis</subject><subject>Critical Illness</subject><subject>Diabetes</subject><subject>Diabetes therapy</subject><subject>Dietary fiber</subject><subject>Electrolytes</subject><subject>Female</subject><subject>Forkhead protein</subject><subject>FOXO1 protein</subject><subject>FOXO3 protein</subject><subject>Gene expression</subject><subject>Glucose</subject><subject>Glycogen</subject><subject>Glycogen synthase kinase 3</subject><subject>Glycogen synthesis</subject><subject>Hospital patients</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Illnesses</subject><subject>Inflammation</subject><subject>Insulin</subject><subject>Insulin-like growth factor I</subject><subject>Insulin-like growth factors</subject><subject>Interleukin</subject><subject>Interleukin 6</subject><subject>Interleukins</subject><subject>Kinases</subject><subject>Male</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Middle Aged</subject><subject>Mortality</subject><subject>Muscle Proteins - genetics</subject><subject>Muscle Proteins - metabolism</subject><subject>Muscle, Skeletal - metabolism</subject><subject>Muscles</subject><subject>Musculoskeletal system</subject><subject>Myostatin</subject><subject>Orthopedics</subject><subject>Pathways</subject><subject>Patients</subject><subject>Phosphates</subject><subject>Phosphorylation</subject><subject>Polymerase chain reaction</subject><subject>Protein binding</subject><subject>Protein Biosynthesis</subject><subject>Protein synthesis</subject><subject>Protein turnover</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Rapamycin</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Ribosomal protein S6</subject><subject>Ribosomal protein S6 kinase</subject><subject>RNA</subject><subject>Rodents</subject><subject>Sepsis</subject><subject>Signal transduction</subject><subject>Signal Transduction - genetics</subject><subject>Signal Transduction - physiology</subject><subject>Signaling</subject><subject>Skeletal muscle</subject><subject>Thigh</subject><subject>TOR protein</subject><subject>Translation (Genetics)</subject><subject>Type 2 diabetes</subject><subject>Western 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protein synthesis and suppressed protein breakdown signaling in skeletal muscle of critically ill patients</title><author>Jespersen, Jakob G ; Nedergaard, Anders ; Reitelseder, Søren ; Mikkelsen, Ulla R ; Dideriksen, Kasper J ; Agergaard, Jakob ; Kreiner, Frederik ; Pott, Frank C ; Schjerling, Peter ; Kjaer, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c691t-f656fe82b82429da7344fb8ce8abf5b269fd8824c0f4c1c8a7a51b539eb498273</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aging</topic><topic>AKT protein</topic><topic>Alcohol</topic><topic>Amino acids</topic><topic>Biology</topic><topic>Blotting, Western</topic><topic>Bone surgery</topic><topic>Branched chain amino acids</topic><topic>Breakdown</topic><topic>Care and treatment</topic><topic>Case-Control Studies</topic><topic>Cell cycle</topic><topic>Chain branching</topic><topic>Comparative analysis</topic><topic>Critical Illness</topic><topic>Diabetes</topic><topic>Diabetes therapy</topic><topic>Dietary fiber</topic><topic>Electrolytes</topic><topic>Female</topic><topic>Forkhead protein</topic><topic>FOXO1 protein</topic><topic>FOXO3 protein</topic><topic>Gene expression</topic><topic>Glucose</topic><topic>Glycogen</topic><topic>Glycogen synthase kinase 3</topic><topic>Glycogen synthesis</topic><topic>Hospital patients</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Illnesses</topic><topic>Inflammation</topic><topic>Insulin</topic><topic>Insulin-like growth factor I</topic><topic>Insulin-like growth factors</topic><topic>Interleukin</topic><topic>Interleukin 6</topic><topic>Interleukins</topic><topic>Kinases</topic><topic>Male</topic><topic>Medicine</topic><topic>Metabolism</topic><topic>Middle Aged</topic><topic>Mortality</topic><topic>Muscle Proteins - genetics</topic><topic>Muscle Proteins - 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Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jespersen, Jakob G</au><au>Nedergaard, Anders</au><au>Reitelseder, Søren</au><au>Mikkelsen, Ulla R</au><au>Dideriksen, Kasper J</au><au>Agergaard, Jakob</au><au>Kreiner, Frederik</au><au>Pott, Frank C</au><au>Schjerling, Peter</au><au>Kjaer, Michael</au><au>Agarwal, Sudha</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activated protein synthesis and suppressed protein breakdown signaling in skeletal muscle of critically ill patients</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-03-31</date><risdate>2011</risdate><volume>6</volume><issue>3</issue><spage>e18090</spage><epage>e18090</epage><pages>e18090-e18090</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β) and forkhead box O (FoxO) pathways, but it is unknown how these pathways are regulated in critically ill human muscle. To describe factors involved in muscle mass regulation, we investigated the phosphorylation and expression of key factors in these protein synthesis and breakdown signaling pathways in thigh skeletal muscle of critically ill intensive care unit (ICU) patients compared with healthy controls.
ICU patients were systemically inflamed, moderately hyperglycemic, received insulin therapy, and showed a tendency to lower plasma branched chain amino acids compared with controls. Using Western blotting we measured Akt, GSK3β, mTOR, ribosomal protein S6 kinase (S6k), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), and muscle ring finger protein 1 (MuRF1); and by RT-PCR we determined mRNA expression of, among others, insulin-like growth factor 1 (IGF-1), FoxO 1, 3 and 4, atrogin1, MuRF1, interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and myostatin. Unexpectedly, in critically ill ICU patients Akt-mTOR-S6k signaling was substantially higher compared with controls. FoxO1 mRNA was higher in patients, whereas FoxO3, atrogin1 and myostatin mRNAs and MuRF1 protein were lower compared with controls. A moderate correlation (r2=0.36, p<0.05) between insulin infusion dose and phosphorylated Akt was demonstrated.
We present for the first time muscle protein turnover signaling in critically ill ICU patients, and we show signaling pathway activity towards a stimulation of muscle protein synthesis and a somewhat inhibited proteolysis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21483870</pmid><doi>10.1371/journal.pone.0018090</doi><tpages>e18090</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-03, Vol.6 (3), p.e18090-e18090 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1292654898 |
| 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 | Adult Aged Aging AKT protein Alcohol Amino acids Biology Blotting, Western Bone surgery Branched chain amino acids Breakdown Care and treatment Case-Control Studies Cell cycle Chain branching Comparative analysis Critical Illness Diabetes Diabetes therapy Dietary fiber Electrolytes Female Forkhead protein FOXO1 protein FOXO3 protein Gene expression Glucose Glycogen Glycogen synthase kinase 3 Glycogen synthesis Hospital patients Hospitals Humans Illnesses Inflammation Insulin Insulin-like growth factor I Insulin-like growth factors Interleukin Interleukin 6 Interleukins Kinases Male Medicine Metabolism Middle Aged Mortality Muscle Proteins - genetics Muscle Proteins - metabolism Muscle, Skeletal - metabolism Muscles Musculoskeletal system Myostatin Orthopedics Pathways Patients Phosphates Phosphorylation Polymerase chain reaction Protein binding Protein Biosynthesis Protein synthesis Protein turnover Proteins Proteolysis Rapamycin Reverse Transcriptase Polymerase Chain Reaction Ribosomal protein S6 Ribosomal protein S6 kinase RNA Rodents Sepsis Signal transduction Signal Transduction - genetics Signal Transduction - physiology Signaling Skeletal muscle Thigh TOR protein Translation (Genetics) Type 2 diabetes Western blotting |
| title | Activated protein synthesis and suppressed protein breakdown signaling in skeletal muscle of critically ill patients |
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