Our long-term goal is to significantly impact the knowledge of muscle biology and provide new approaches for disease treatment. Striated muscle fibers are large multinucleated cells and possess a highly organized cytoarchitecture containing organelles positioned for optimal muscle function. This positioning is particularly evident in the placement of myonuclei, which reside above the sarcomere at the periphery of the myofiber and are positioned to maximize their internuclear distance. Our objective is the identification of mechanisms responsible for myonuclear movement and positioning. Centrally located myonuclei have been used for decades as a hallmark of muscle disease. However, little is known about the mechanisms that control myonuclear movement normally, or the contribution of aberrant myonuclear position to the etiology and/or progression of muscle disease. Building on our recently published results (Metzger et al., Nature, 2012;Folker et al., Development, 2012), our specific aims in this proposal are to characterize new genes involved in myonuclear positioning, address how tendon and motorneurons fine-tune myonuclear positioning during muscle function, and investigate why muscles fail to function optimally when myonuclei are mispositioned. This proposal will identify physiological changes that result from aberrant nuclear placement, providing new biomarkers/therapeutic targets to examine/treat muscle disease. Lastly, these data will shed light on how the organization of the muscle fiber cytoarchitecture is achieved during development and growth. Our investigation will be primarily carried out in Drosophila;however, we will test our paradigm in mammalian muscle cultures. Our methodologies take advantage of cutting edge, in vivo time lapse imaging that we have developed in Drosophila to follow myonuclear movement and cytoskeletal dynamics. We will employ the genetic resources available in Drosophila to manipulate genes, processes, and cell types for our analyses. These genetic experiments will be supported by biochemical and cell biological approaches. Muscle physiology will be investigated by assaying mitochondrial output via quantification of ATP and ROS levels, including using a novel ROS sensor for the latter, and neuromuscular communication, and importantly muscle cellular output, via electrophysiological approaches. Genomic approaches, specifically RNAseq, will reveal changes in the muscle transcriptome as a result of improper myonuclear position. Together the work outlined in this proposal will shed new light on this little understood but important area of muscle biology. The results of this research will permit us to highlight genes and mechanisms that are candidates for changes associated with different human muscle diseases.

Public Health Relevance

Our research will significantly impact the knowledge of muscle biology and provide new approaches for human disease treatment. Specifically, we will identify mechanisms responsible for movement and position of muscle cell nuclei to understand how improper positioning of muscle nuclei can occur, and how improper positioning impacts normal cell function. The results of this research will permit us to highlight the genes and cellulr mechanisms that fail to function properly in human muscle diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
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Boyce, Amanda T
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New York
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Balakrishnan, Mridula; Baylies, Mary K (2018) Myonuclear Positioning and Aneurysms Are LINC'd by Ariande. Dev Cell 45:149-150
Deng, Su; Azevedo, Mafalda; Baylies, Mary (2017) Acting on identity: Myoblast fusion and the formation of the syncytial muscle fiber. Semin Cell Dev Biol 72:45-55
Rosen, Jonathan N; Baylies, Mary K (2017) Myofibrils put the squeeze on nuclei. Nat Cell Biol 19:1148-1150
Deng, Su; Bothe, Ingo; Baylies, Mary (2016) Diaphanous regulates SCAR complex localization during Drosophila myoblast fusion. Fly (Austin) 10:178-86
Azevedo, Mafalda; Schulman, Victoria K; Folker, Eric et al. (2016) Imaging Approaches to Investigate Myonuclear Positioning in Drosophila. Methods Mol Biol 1411:291-312
Bothe, Ingo; Baylies, Mary K (2016) Drosophila myogenesis. Curr Biol 26:R786-91
Deng, Su; Bothe, Ingo; Baylies, Mary K (2015) The Formin Diaphanous Regulates Myoblast Fusion through Actin Polymerization and Arp2/3 Regulation. PLoS Genet 11:e1005381
Dobi, Krista C; Schulman, Victoria K; Baylies, Mary K (2015) Specification of the somatic musculature in Drosophila. Wiley Interdiscip Rev Dev Biol 4:357-75
Schulman, Victoria K; Dobi, Krista C; Baylies, Mary K (2015) Morphogenesis of the somatic musculature in Drosophila melanogaster. Wiley Interdiscip Rev Dev Biol 4:313-34
Kumar, Ram P; Dobi, Krista C; Baylies, Mary K et al. (2015) Muscle cell fate choice requires the T-box transcription factor midline in Drosophila. Genetics 199:777-91

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