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Screening for Mediators of Cardiac Function and Systemic Metabolism to Increase Longevity and Healthspan

  • Author(s): Min, Peter
  • Advisor(s): Engler, Adam J
  • et al.
Abstract

With age, cardiomyocytes’ regenerative capacity is highly compromised, and among many other maladaptive phenotypes such as hypertrophy, the total number of cardiomyocytes begins to diminish. To compensate for the heavier load and mechanical demand placed on the remaining cardiomyocytes, vinculin has been shown to be upregulated with age in the heart across organisms. In Drosophila Melanogaster, vinculin localizes at the intercalated discs (ICD) and costameres to help sustain the sarcomere lattice structure and generate a higher force production. In Aim 1, we tried to confer a similar improvement in cardiac function through therapeutic intervention. We screened several drugs that have been selected from Ingenuity Pathway Analysis (IPA), such as forskolin, a potent adenylyl

cyclase activator, and drugs that target the nitric oxide(NO)-cGMP pathway. Screening methods included both in vitro screening in S2R+ cells and in vivo treatment in wild-type flies. We have found that neither administrating forskolin nor targeting the NO pathway increases vinculin expression or localization in flies. Next, we wanted to investigate the relationship between cardiac contractility and systemic metabolism. In Aim 2, we validated that we can trace the metabolism of 13C-labeled glucose in the whole-fly. This allows for the investigation of differences in the glucose metabolism between the two genetic lines (vinculin-overexpressing line and the control line) across different ages. In Aim 3, we observed that impairing cellular respiration alone via treatment with a mitochondrial inhibitor is sufficient to bring about drastic cytoskeletal changes in S2R+ cells and, subsequently, mechanical function in dissected fly hearts.

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