Mitogen-activated protein kinase-activated protein kinases 2 and 3 regulate SERCA2a expression and fiber type composition to modulate skeletal muscle and cardiomyocyte function.
Mol Cell Biol
; 33(13): 2586-602, 2013 Jul.
Article
em En
| MEDLINE
| ID: mdl-23608535
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
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Músculo Esquelético
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Miócitos Cardíacos
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Peptídeos e Proteínas de Sinalização Intracelular
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ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Mol Cell Biol
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Alemanha