# Mechanogenetics: An Integrated Approach to Aging in Muscle Dysfunction

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $395,018

## Abstract

Project Summary
Cardiac performance declines with age, but genetic variation within a population makes it difficult to identify the
conserved aging mechanisms that negatively impact mechanical function, i.e. mechanogenetics. Over the past
5 years, we have studied cardiac function of the rapidly aging Drosophila melanogaster across many
laboratory fruit fly strains. We found that fly strains with age-dependent and heart-specific vinculin up-
regulation use it to reinforce and stiffen their costameres and intercalated discs, which helps maintain the
crystallinity of their sarcomere lattice and improves contractility. At the cardiomyocyte level, maintaining inter-
myofilament spacing prolongs wall shortening velocity and fractional shortening, and systemically, it extends
lifespan. Fly strains with decreased basement membrane (BM) protein expression, e.g. laminin, also exhibit
similar systemic benefits but due to thinner extracellular matrix, which improves cell-cell coupling between
adjacent myocyte layers; importantly, both vinculin up-regulation and BM down-regulation with age appear
conserved up through non-human primates. Together these data suggest a new inside-outside aging paradigm
that prolongs heart function, i.e. a robust internal contractile apparatus with limited extracellular connections to
BM. In this grant application, we propose further aims to determine how these intracellular and extracellular
heart perturbations act combinatorially to alter function across cellular-, tissue-, and organ-levels. Preliminary
assessments in transgenic fly strains suggest that more efficient cardiomyocyte contraction, may improve
substrate utilization and oxygen consumption within fly hearts, and subsequently organ perfusion and systemic
metabolism, and better health- and lifespan. In light of this paradigm and the challenges that mechanogenetics
present, we have developed new biological and analytical tools for this grant that will improve the feasibility of
assessing the age-related mechanical differences of Drosophila myocardium between wild-type and transgenic
lines. Thus, this on-going work will continue to improve our understanding of the inside-outside aging
paradigm.

## Key facts

- **NIH application ID:** 10170164
- **Project number:** 5R01AG045428-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Adam J Engler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,018
- **Award type:** 5
- **Project period:** 2013-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170164

## Citation

> US National Institutes of Health, RePORTER application 10170164, Mechanogenetics: An Integrated Approach to Aging in Muscle Dysfunction (5R01AG045428-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10170164. Licensed CC0.

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