MEF2 and HDAC Proteins Regulate Striated Muscle Development and Remodeling
Potthoff, Matthew Joseph
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The establishment of different tissues during embryogenesis requires coupling of upstream signal transduction pathways with networks of transcription factors that govern cell differentiation and morphogenesis. The myocyte enhancer factor 2 (MEF2) transcription factor acts as a lynchpin in the transcriptional circuits that control differentiation of diverse cell types including skeletal, cardiac and smooth muscle cells, neurons, chondrocytes, lymphocytes, endothelial cells and neural crest cells. Class II histone deacetylase (HDAC) proteins bind to MEF2 and regulate MEF2 activity in response to various signaling cascades. To understand the role of MEF2 and class II HDAC proteins in skeletal muscle development and remodeling, we analyzed individual MEF2 knockout mice, HDAC knockout mice, and compound mutant mice. We discovered that skeletal muscle-specific deletion of Mef2c in mice results in disorganized myofibers and perinatal lethality. In contrast, neither Mef2a nor Mef2d are required for normal skeletal muscle development in vivo. Skeletal muscle deficient in Mef2c differentiates and forms normal myofibers during embryogenesis, but myofibers rapidly deteriorate after birth due to disorganized sarcomeres and a loss of integrity of the M-line. We discovered that MEF2C directly regulates important structural genes required for the maintenance of sarcomere integrity and postnatal maturation of skeletal muscle. To address the function of class II HDACs and MEF2 proteins in adult skeletal muscle remodeling, we discovered that class II HDAC proteins, which function as transcriptional repressors of the MEF2 transcription factor, fail to accumulate in the soleus, a slow-twitch muscle, compared to fast-twitch muscles (eg.., white vastus lateralis). Using gain- and loss-offunction approaches in mice, we discovered that class II HDAC proteins suppress slow, oxidative myofiber identity through the repression of MEF2 activity. Conversely, expression of a hyperactive form of MEF2 in skeletal muscle of transgenic mice promotes the slow fiber phenotype and enhances running endurance, enabling mice to run almost twice the distance of wild type littermates. Thus, the selective degradation of class II HDACs in slow skeletal muscle provides a mechanism for enhancing physical performance and resistance to fatigue by augmenting the transcriptional activity of MEF2. To understand the functions of class I HDACs in cardiac development and remodeling, we generated cardiac-specific HDAC1 and HDAC3 transgenic mice. Overexpression of HDAC1 resulted in a dilated cardiomyopathy, while overexpression of HDAC3 produced a stress-induced cardiac phenotype. We establish an important role for these proteins in cardiac remodeling and provide potential mechanisms regulating these enzymes in vivo. Taken together, these studies demonstrate an important role for MEF2 and HDAC proteins in muscle development and function. Moreover, these results provide important mechanistic insights into the regulation of MEF2 and HDAC proteins in vivo.