# T-tubule membrane remodeling in Drosophila myofiber function and models of myopathy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $337,172

## Abstract

Project Summary
Muscles are highly specialized and organized cells that provide contraction essential for animal life. A
disruption of the elaborate, functional muscle cell organization underlies human myopathy diseases. In
particular, differentiation of the muscle cell membrane into an extensive tubular membrane network called
Transverse (T)-tubules is needed to enable signaling that coordinates power of muscle contraction. T-tubule
disorganization or loss is observed in certain human skeletal myopathies and cardiovascular diseases, and
interestingly, associated mutant genes encode for membrane regulators with known wildtype roles outside of
muscle in endocytosis or endosomal trafficking. While there are speculations on mechanisms, it remains to be
determined how implicated endocytic functions may contribute to T-tubule maintenance. Relatively little is
known about the molecular-genetic basis for how T-tubules form nor the dynamics or remodeling mechanisms
in intact muscle in response to muscle cell use, damage or aging. In flies, we uncovered regulated T-tubule
remodeling and the identity of specific conserved gene functions involved at distinct disassembly-reassembly
stages during a wildtype developmental myofiber remodeling program. Importantly, specific T-tubule
remodeling roles for fly homologs of two human genes disrupted in centronuclear myopathy point to the
significance of T-tubule dynamics and the ability to study in models of disease. The fly system affords the
unique and key advantages of live, in vivo imaging of T-tubule dynamics in intact myofibers within a
stereotypical developmental timeframe in combination with a wealth of genetic tools. Following results from
genetic screens, we established a new framework understanding of T-tubule dynamics that includes a central
role for dynamin large GTPase activity in T-tubule disassembly and subsequent membrane progression into
specific endosomal and autophagy trafficking needed for remodeling. Using our innovative genetic, cellular and
molecular approaches in intact fly muscles, here we will build on our novel findings to determine the
mechanisms and regulation of dynamin-mediated T-tubule disassembly by vesiculation, and establish the
identity of a proposed novel Rab35 endosomal pathway and the relationship to autophagy both needed for
progression from disassembly to remodeling. Importantly, we will translate our understanding of a
developmental program for T-tubule remodeling to adult flight muscle. We will establish conservation and
consequences of a pathway activity for T-tubule membrane reorganization in ongoing adult muscle function,
with relevance to understanding human muscle disease.

## Key facts

- **NIH application ID:** 10203829
- **Project number:** 5R01AR073840-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** AMY A KIGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $337,172
- **Award type:** 5
- **Project period:** 2018-08-09 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10203829

## Citation

> US National Institutes of Health, RePORTER application 10203829, T-tubule membrane remodeling in Drosophila myofiber function and models of myopathy (5R01AR073840-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10203829. Licensed CC0.

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