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.
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. We demonstrated 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 that MK2 catalytic activity directly regulated the promoters of the fast fiber-specific myosin heavy-chain IId/x and the slow fiber-specific sarco/endoplasmic reticulum Ca(2+)-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.
authors.affiliation: Department of Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Scharf
authors.forename: Stefan
authors.initials: S
authors.lastname: Neef
authors.forename: Robert
authors.initials: R
authors.lastname: Freund
authors.forename: Cornelia
authors.initials: C
authors.lastname: Geers-Knörr
authors.forename: Mirita
authors.initials: M
authors.lastname: Franz-Wachtel
authors.forename: Almuth
authors.initials: A
authors.lastname: Brandis
authors.forename: Dorothee
authors.initials: D
authors.lastname: Krone
authors.forename: Heike
authors.initials: H
authors.lastname: Schneider
authors.forename: Stephanie
authors.initials: S
authors.lastname: Groos
authors.forename: Manoj B
authors.initials: MB
authors.lastname: Menon
authors.forename: Kin-Chow
authors.initials: KC
authors.lastname: Chang
authors.forename: Theresia
authors.initials: T
authors.lastname: Kraft
authors.forename: Joachim D
authors.initials: JD
authors.lastname: Meissner
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Boheler
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.forename: Renate J
authors.initials: RJ
authors.lastname: Scheibe
mesh_terms: D000818:Animals; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D048291:Mitogen-Activated Protein Kinase 12; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D009119:Muscle Contraction / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D051766:Early Growth Response Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D048291:Mitogen-Activated Protein Kinase 12; D048308:Mitogen-Activated Protein Kinase 14; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017346:Protein Serine-Threonine Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015534:Trans-Activators; D014157:Transcription Factors; D000099190:MAP-Kinase-Activated Kinase 2; C486109:Egr1 protein, mouse; C485290:Ppargc1a protein, mouse; C098416:MAP-kinase-activated kinase 3