(Downloading may take up to 30 seconds.
If the slide opens in your browser, select File -> Save As to save it.)
Click on image to view larger version.
FIG. 1. Myocyte enhancer factor 2 (MEF2) participates in transducing adenosine triphosphate (ATP) and calcium signals to mediate hypertrophic gene expression. In response to increased workload or stress (e.g., inefficient coupling of excitation and contraction, inefficient contraction due to genetic defect), ATP levels fall and intracellular calcium concentration rises. The rise in intracellular calcium may be exacerbated when ATP levels are low due to reduced activity of calcium pumps in the sarcolemma or sarcoplasmic reticulum, resulting in reduced calcium sequestration during relaxation. Increased adenosine monophosphate (AMP):ATP ratio activates AMP-activated protein kinase (AMPK) kinase, or AMPK directly, while at the same time, increased calcium concentration activates calcium/calmodulin-dependent protein kinase (CaMK) kinase and calmodulin, which, in turn, activate CaM kinases. Activated CaMKs activate MEF2-regulated transcription by phosphorylating histone deacetylases (HDACs), which repress MEF2 transactivation, resulting in HDAC release from MEF2 and export of HDACs from the nucleus by 14-3-3. Activated AMPK increases transcription of peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1
(PGC-1) and MEF2A and MEF2D via an unknown mechanism. PGC-1 also coactivates its own expression, ostensibly mediated by MEF2. PGC-1 and PPAR
cooperate to drive expression of fatty acid oxidation enzymes and promote mitochondrial biogenesis. PGC-1 and MEF2 cooperate to drive expression of GLUT4, thereby increasing glycolysis and/or glucose oxidation by augmenting glucose import, and may participate in driving expression of genes involved in hypertrophy such as contractile proteins. Increased intracellular calcium concentration and activation of calmodulin also activate the protein phosphatase calcineurin, which dephosphorylates and activates the nuclear factor of activated T cell (NFAT) transcription factor family that is involved in driving the hypertrophic program. Calcineurin may activate MEF2 directly but the mechanism of this process has not been elucidated. Numerous other signaling pathways are expected to interact with components of this model — for example, the phosphatidylinositol 3-kinase/glycogen synthase kinase-3ß (PI-3K/GSK-3ß) pathway — since GSK-3ß regulates NFAT transcriptional activity.
