Genetic regulation of muscle fiber diversity

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The long-term objectives of this application are to understand how individual muscles assume their unique characteristics in the body, and to identify the factors which direct myoblasts towards these unique fates. All muscle cells in the body have characteristics which broadly classify them as fast or slow fibers, yet we still have a lot to learn in terms of how fiber identity is initially determined. Here, we shall use the model animal Drosophila, where the muscles of the adult thorax assume two distinct phenotypes: the fibrillar muscles which power flight; and the tubular muscles which are required for walking and jumping. Our research so far has identified the myogenic factor myocyte enhancer factor-2 (MEF2) as an important regulator of the patterning of these muscles, and in this application we shall define in detail how MEF2 functions in adult muscle development, and identify genes through which MEF2 works to control fiber patterning. Our current work has also identified a number of enhancer elements which show activity which is restricted either to the fibrillar or tubular muscles. We posit that regulators of these enhancers are critical determinants of specific muscle identities, therefore we shall identify the transcriptional regulators acting upon these enhancer and define their role in muscle development and the generation of muscle fiber diversity. These studies will define important regulatory mechanisms used to diversify the muscle lineage in animals, and given the strong evolutionary conservation in developmental mechanisms, our results will have broad relevance to the formation of muscles in higher animals, including vertebrates. We hope that the findings of our basic research will ultimately lead to new mechanisms and paradigms to comprehend how mammalian muscles form and how muscle development and function goes awry in the diseased state. Relevance to public health: This research will tell us how genes work together to make muscles in the body. Since the genes that make muscles in flies are strikingly similar to those that function in higher animals including humans, our findings will help us to understand how human muscles are formed and how specific muscles in the body function in the way that they do. We anticipate that the results of our research will allow other to better understand how muscles form, and how muscles might be disrupted under disease conditions.