Regulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and mitochondrial function by MEF2 and HDAC5

Michael P. Czubryt, John McAnally, Glenn I. Fishman, Eric N. Olson

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Abstract

The myocyte enhancer factor-2 (MEF2) transcription factor regulates muscle development and calcium-dependent gene expression. MEF2 activity is repressed by class II histone deacetylases (HDACs), which dissociate from MEF2 when phosphorylated on two serine residues in response to calcium signaling. To explore the potential importance of MEF2/HDAC interactions in the heart, we generated transgenic mice expressing a signal-resistant form of HDAC5 under cardiac-specific and doxycycline-inducible regulation. Transgene expression resulted in sudden death in male mice accompanied by loss and morphologic changes of cardiac mitochondria and down-regulation of mitochondrial enzymes. The transcriptional coactivator PGC-1α, a master regulator of mitochondrial biogenesis and fatty acid oxidation, was also down-regulated in response to HDAC5 expression. Examination of the PGC-1α promoter revealed two MEF2-binding sites that mediate transcriptional activation by MEF2 and repression by HDAC5. These findings identify PGC-1α as a key target of the MEF2/HDAC regulatory pathway and demonstrate this pathway's importance in maintenance of cardiac mitochondrial function.

Original languageEnglish (US)
Pages (from-to)1711-1716
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number4
DOIs
StatePublished - Feb 18 2003

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