Mechanogenetics: An Integrated Approach in Muscle Dysfunction

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Cardiac performance declines with age and has been attributed to the accumulation of abnormal gene changes. The cardiac aging paradigm has postulated that these changes ultimately perturb myocyte stiffness and cytoskeletal organization leading to systolic and/or diastolic dysfunction. However efforts to understand dysfunction have been stymied by at least three factors: 1) mechanogenetics, i.e. the genetic variation within a model organism affecting mechanical function making it difficult to identify conserved aging mechanisms, 2) geometric complexity of model organisms, and 3) extremely gradual aging. We have developed novel approaches to measure the passive and active mechanics and physiology of fruit flies, i.e. Drosophila melanogaster, a model system that rapidly ages from juvenile to geriatric in 6 weeks. Using these new analysis methods and the high throughput nature of the Drosophila model, we will examine how genotypic variation influences cardiac aging, and we will also identify what mammalian-conserved genes are most responsible for these detrimental changes leading to dysfunction via microarrays, qPCR, and western blotting. Using targeted molecular genetics, we will subsequently assess the influence of these specific genes on age-related myocyte remodeling, e.g. changes in expression of sarcomeric, costameric, and junctional proteins, as well as how they alter adhesion between the adjacent ventral muscle and heart tube. Importantly, we will also assess how these genes alter fly heart physiology and function. Comparison with aging databanks of conventional models will ensure that these Drosophila data provide meaningful predictions for the genes responsible in part for age- related dysfunction. This Drosophila work will provide the first in vivo analysis and dissection of the mechanics and function of rapidly aging myocardium in a high throughput fashion and it will also identify genetic modulators and potential therapeutic targets that could improve cardiovascular aging.