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-1 α promoter revealed two MEF2-binding sites that mediate transcriptional activation by MEF2 and repression by HDAC5. These findings identify PGC-1 α as a key target of the MEF2/HDAC regulatory pathway and demonstrate this pathway's importance in maintenance of cardiac mitochondrial function.

Serum response factor (SRF) controls the transcription of muscle genes by recruiting a variety of partner proteins, including members of the myocardin family of transcriptional coactivators. Mice lacking SRF fail to form mesoderm and die before gastrulation, precluding an analysis of the roles of SRF in muscle tissues. To investigate the functions of SRF in skeletal muscle development, we conditionally deleted the Srf gene in mice by skeletal muscle-specific expression of Cre recombinase. In mice lacking skeletal muscle SRF expression, muscle fibers formed, but failed to undergo hypertrophic growth after birth. Consequently, mutant mice died during the perinatal period from severe skeletal muscle hypoplasia. The myopathic phenotype of these mutant mice resembled that of mice expressing a dominant negative mutant of a myocardin family member in skeletal muscle. These findings reveal an essential role for the partnership of SRF and myocardin-related transcription factors in the control of skeletal muscle growth and maturation in vivo .