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- Publisher Website: 10.1128/MCB.01692-12
- Scopus: eid_2-s2.0-84880653056
- PMID: 23608535
- WOS: WOS:000320030900007
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Article: Mitogen-activated protein kinase-activated protein kinases 2 and 3 regulate serca2a expression and fiber type composition to modulate skeletal muscle and cardiomyocyte function
Title | Mitogen-activated protein kinase-activated protein kinases 2 and 3 regulate serca2a expression and fiber type composition to modulate skeletal muscle and cardiomyocyte function |
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Authors | |
Issue Date | 2013 |
Citation | Molecular and Cellular Biology, 2013, v. 33 n. 13, p. 2586-2602 How to Cite? |
Abstract | The mitogen-activated protein kinase (MAPK)-activated protein kinases 2 and 3 (MK2/3) represent protein kinases downstream of the p38 MAPK. Using MK2/3 double-knockout (MK2/3-/-) mice, we analyzed the role of MK2/3 in cross-striated muscle by transcriptome and proteome analyses and by histology. Wedemonstrated enhanced expression of the slow oxidative skeletal muscle myofiber gene program, including the peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α(PGC-1α). Using reporter gene and electrophoretic gel mobility shift assays, we demonstrated thatMK2catalytic activity directly regulated the promoters of the fast fiber-specific myosin heavy-chain IId/x and the slow fiber-specific sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) gene. Elevated SERCA2a gene expression caused by a decreased ratio of transcription factor Egr-1 to Sp1 was associated with accelerated relaxation and enhanced contractility in MK2/3-/- cardiomyocytes, concomitant with improved force parameters in MK2/3-/- soleus muscle. These results link MK2/3 to the regulation of calcium dynamics and identify enzymatic activity of MK2/3 as a critical factor for modulating cross-striated muscle function by generating a unique muscle phenotype exhibiting both reduced fatigability and enhanced force in MK2/3-/- mice. Hence, the p38-MK2/3 axis may represent a novel target for the design of therapeutic strategies for diseases related to fiber type changes or impaired SERCA2 function. © 2013, American Society for Microbiology. All Rights Reserved. |
Persistent Identifier | http://hdl.handle.net/10722/195145 |
ISSN | 2023 Impact Factor: 3.2 2023 SCImago Journal Rankings: 1.452 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Scharf, M | - |
dc.contributor.author | Neef, S | - |
dc.contributor.author | Freund, R | - |
dc.contributor.author | Geers-Knörr, C | - |
dc.contributor.author | Franz-Wachtel, M | - |
dc.contributor.author | Brandis, A | - |
dc.contributor.author | Krone, D | - |
dc.contributor.author | Schneider, H | - |
dc.contributor.author | Groos, S | - |
dc.contributor.author | Menon, MB | - |
dc.contributor.author | Chang, K-C | - |
dc.contributor.author | Kraft, T | - |
dc.contributor.author | Meissner, JD | - |
dc.contributor.author | Boheler, KR | - |
dc.contributor.author | Maier, LS | - |
dc.contributor.author | Gaestel, M | - |
dc.contributor.author | Scheibe, RJ | - |
dc.date.accessioned | 2014-02-25T01:40:14Z | - |
dc.date.available | 2014-02-25T01:40:14Z | - |
dc.date.issued | 2013 | - |
dc.identifier.citation | Molecular and Cellular Biology, 2013, v. 33 n. 13, p. 2586-2602 | - |
dc.identifier.issn | 0270-7306 | - |
dc.identifier.uri | http://hdl.handle.net/10722/195145 | - |
dc.description.abstract | The mitogen-activated protein kinase (MAPK)-activated protein kinases 2 and 3 (MK2/3) represent protein kinases downstream of the p38 MAPK. Using MK2/3 double-knockout (MK2/3-/-) mice, we analyzed the role of MK2/3 in cross-striated muscle by transcriptome and proteome analyses and by histology. Wedemonstrated enhanced expression of the slow oxidative skeletal muscle myofiber gene program, including the peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α(PGC-1α). Using reporter gene and electrophoretic gel mobility shift assays, we demonstrated thatMK2catalytic activity directly regulated the promoters of the fast fiber-specific myosin heavy-chain IId/x and the slow fiber-specific sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) gene. Elevated SERCA2a gene expression caused by a decreased ratio of transcription factor Egr-1 to Sp1 was associated with accelerated relaxation and enhanced contractility in MK2/3-/- cardiomyocytes, concomitant with improved force parameters in MK2/3-/- soleus muscle. These results link MK2/3 to the regulation of calcium dynamics and identify enzymatic activity of MK2/3 as a critical factor for modulating cross-striated muscle function by generating a unique muscle phenotype exhibiting both reduced fatigability and enhanced force in MK2/3-/- mice. Hence, the p38-MK2/3 axis may represent a novel target for the design of therapeutic strategies for diseases related to fiber type changes or impaired SERCA2 function. © 2013, American Society for Microbiology. All Rights Reserved. | - |
dc.language | eng | - |
dc.relation.ispartof | Molecular and Cellular Biology | - |
dc.title | Mitogen-activated protein kinase-activated protein kinases 2 and 3 regulate serca2a expression and fiber type composition to modulate skeletal muscle and cardiomyocyte function | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1128/MCB.01692-12 | - |
dc.identifier.pmid | 23608535 | - |
dc.identifier.scopus | eid_2-s2.0-84880653056 | - |
dc.identifier.volume | 33 | - |
dc.identifier.issue | 13 | - |
dc.identifier.spage | 2586 | - |
dc.identifier.epage | 2602 | - |
dc.identifier.isi | WOS:000320030900007 | - |
dc.identifier.issnl | 0270-7306 | - |