Regulation of mitochondrial function by Myocardin during cardiac development and disease
Metabolic specific myogenic precursors in the splanchnic, somatic mesoderm, and the neural crest give rise to specialized cell types such as cardiac, skeletal, and smooth muscle cells. This initiation of muscle cell lineage is coordinated by a reinforcing networking of transcription factors that regulate gene expression during cell proliferation and differentiation. Myocardin is a transcriptional coactivator that binds to transcription factors to regulate gene expression specific to both cardiac and smooth muscle cells. It is previously shown that Myocardin interacts with transcription factors of the MADS-Box family proteins such as myocyte enhancer factor-2 (MEF2) and serum response factor (SRF), that are known regulators of cellular differentiation and metabolism. Conversely, the role of Myocardin as well as its regulation of MADS-Box transcription factors and mitochondrial function during development and disease is not well understood. Therefore, we chose to investigate a Myocardin-regulated genetic pathway that regulates mitochondrial function in cardiac muscle that becomes dysregulated during disease. My thesis summarizes our evaluation of the hypothesis in two studies. In the first study we characterize a mechanistic pathway involving MEF2 and SRF, that regulates mitochondrial function in all three muscle lineages. This initial study demonstrates a genetic pathway in which Nix is a direct target of miR-133a, its role in regulating insulin sensitivity and metabolic dysfunction in myocytes. These novel findings lead to my second study that examines the role of Myocardin in regulating miR-133a and Nix in cardiac cells. I provide evidence that miR−133a is a direct transcriptional target of Myocardin that regulates mitochondrial permeability transition to preserve cell survival during cardiac development and following myocardial ischemic injury. iii Together, these findings inform researchers about the vital role of a Myocardin-regulated pathway that maintains mitochondrial function to oppose cell death during development as novel pharmacotherapy targets. Ongoing investigation is required to further understand miR-133a function as a potential cardiometabolic biomarker or as a therapeutic intervention for the prevention and/or treatment of congenital heart defects, cardiometabolic disease and heart failure.
myocardin, co-activator, cardiac cell biology, cell science, cardiovascular development, mitochondrial function, micro-RNA