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1 Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden; Surgical Sciences, Karolinska Institute, Stockholm, Sweden
2 Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
3 Surgical Sciences, Karolinska Institute, Stockholm, Sweden; Sports University, Stockholm, Sweden
4 Surgical Sciences, Karolinska Institute, Stockholm, Sweden
* To whom correspondence should be addressed. E-mail: Anna.Krook{at}fyfa.ki.se.
The myocyte enhancer factor (MEF)2 transcription factor is important for development of differentiated skeletal muscle. We investigated the regulation of MEF2 DNA binding in differentiated primary human skeletal muscle cells and isolated rat skeletal muscle after exposure to various stimuli. MEF2 DNA binding activity in non-stimulated (basal) muscle cultures was almost undetectable. Exposure of cells for 20 minutes to insulin (120 nM), hydrogen peroxide (0.1 and 1.0 mM), osmotic stress (mannitol 400 mM) or AICAR (1.0 mM) led to a profound increase in MEF2 DNA binding. To study signaling pathways mediating MEF2 activity, human skeletal muscle cell cultures or isolated rat epitrochlearis muscles were pre-incubated with inhibitors of p38 mitogen activated protein kinase (MAPK) (10 µM SB203580), MEK1 (50 µM PD98059), protein kinase C (PKC) (1 and 10µM GF109203X), phosphatidylinositol (PI) 3-kinase (10 µM LY294002), or AMP-activated protein kinase (AMPK) (20 µM Compound C). All stimuli resulted primarily in activation of MEF2D DNA binding. Exposure of cells to osmotic or oxidative stress increased MEF2 DNA binding via pathways that were completely blocked by MAPK inhibitors, and partially blocked by inhibitors of PKC, PI 3-kinase, and AMPK. In epitrochlearis muscle, MAPK inhibitors blocked contraction, but not AICAR-mediated MEF2 DNA binding . Thus activation of MEF2 in skeletal muscle is regulated via parallel intracellular signaling pathways in response to insulin, cellular stress or activation of AMPK.
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