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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

TitleMitogen-activated protein kinase-activated protein kinases 2 and 3 regulate serca2a expression and fiber type composition to modulate skeletal muscle and cardiomyocyte function
Authors
Issue Date2013
Citation
Molecular and Cellular Biology, 2013, v. 33 n. 13, p. 2586-2602 How to Cite?
AbstractThe 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 Identifierhttp://hdl.handle.net/10722/195145
ISSN
2015 Impact Factor: 4.427
2015 SCImago Journal Rankings: 3.806
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorScharf, M-
dc.contributor.authorNeef, S-
dc.contributor.authorFreund, R-
dc.contributor.authorGeers-Knörr, C-
dc.contributor.authorFranz-Wachtel, M-
dc.contributor.authorBrandis, A-
dc.contributor.authorKrone, D-
dc.contributor.authorSchneider, H-
dc.contributor.authorGroos, S-
dc.contributor.authorMenon, MB-
dc.contributor.authorChang, K-C-
dc.contributor.authorKraft, T-
dc.contributor.authorMeissner, JD-
dc.contributor.authorBoheler, KR-
dc.contributor.authorMaier, LS-
dc.contributor.authorGaestel, M-
dc.contributor.authorScheibe, RJ-
dc.date.accessioned2014-02-25T01:40:14Z-
dc.date.available2014-02-25T01:40:14Z-
dc.date.issued2013-
dc.identifier.citationMolecular and Cellular Biology, 2013, v. 33 n. 13, p. 2586-2602-
dc.identifier.issn0270-7306-
dc.identifier.urihttp://hdl.handle.net/10722/195145-
dc.description.abstractThe 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.languageeng-
dc.relation.ispartofMolecular and Cellular Biology-
dc.titleMitogen-activated protein kinase-activated protein kinases 2 and 3 regulate serca2a expression and fiber type composition to modulate skeletal muscle and cardiomyocyte function-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1128/MCB.01692-12-
dc.identifier.pmid23608535-
dc.identifier.scopuseid_2-s2.0-84880653056-
dc.identifier.volume33-
dc.identifier.issue13-
dc.identifier.spage2586-
dc.identifier.epage2602-
dc.identifier.isiWOS:000320030900007-

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