# The contributions of excitation and contraction to muscle deterioration in a Drosophila model of CFL2 nemaline myopathy

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $52,366

## Abstract

PROJECT SUMMARY
Nemaline myopathy (NM) is a skeletal muscle disease hallmarked by muscle weakness with an incidence of 1
in 50,000 live births. On histopathology, there is an obvious presence of actin accumulations in disrupted muscle.
The causative mutations identified thus far are in genes critical for actin filament structure within the muscle, yet
the molecular mechanisms for how alteration of these proteins leads to NM pathology is not well understood.
Cofilin-2, which is important for actin filament severing, is one such affected actin-binding protein. This cofilin
isoform is the predominant form in postnatal and mature skeletal muscle; its function has mainly been studied
with respect to actin at the sarcomere, the muscle’s main contractile unit. Cofilin-2 is known to biochemically
bind more readily to cytoplasmic non-sarcomeric actin than sarcomeric actin, but the impact of this characteristic
on NM progression has not been studied. A Drosophila model of muscle-specific cofilin (DmCFL) knockdown
was shown by our lab to have progressive muscular defects linked to sarcomere addition during growth. I
analyzed RNA sequencing data produced from muscle-enriched preparation of the DmCFL knockdown model
and found that genes associated with excitation-contraction coupling (ECC) are differentially expressed. ECC is
the process by which signals from the motor neuron are communicated to the muscle ultimately leading to
contraction. My preliminary data show disordered actin organization at the muscle side of the neuromuscular
junction (NMJ), which is where the muscle receives signals from the motor neuron. Based on the literature and
these preliminary findings, I hypothesize that cofilin regulation of non-sarcomeric actin is critical for the
proper NMJ and contraction machinery structure needed for ECC prior to muscle deterioration. To
address this hypothesis, I will use the DmCFL knockdown model to analyze the impact of decreased cofilin on
the NMJ signal transduction (Aim 1) and muscle contraction (Aim 2). The former will be accomplished by
using molecular, microscopy, and electrophysiological techniques to analyze changes in NMJ protein
localization, morphology, and function at the muscle (Aim 1A) and motor neuron (Aim 1B). I will compare the
morphological findings from Drosophila larval muscle to those from cofilin-2 knockout mouse muscle samples.
Contraction will be assessed using fluorescent imaging techniques targeted to the calcium signaling machinery
(Aim 2A). Using a modified exercise approach (Aim 2B), I will discover how exercise intensity influences
contraction and phenotype progression in DmCFL knockdown larva. These experiments will collectively provide
insight into the status of the NMJ and contractile activity in cofilin NM while leveraging the simplicity yet high
level of evolutionary conservation of Drosophila. In answering this question relevant to a clinical disease
that typically manifests early in life, I will further develop th...

## Key facts

- **NIH application ID:** 10829207
- **Project number:** 5F30HD111309-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Briana Christophers
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $52,366
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10829207

## Citation

> US National Institutes of Health, RePORTER application 10829207, The contributions of excitation and contraction to muscle deterioration in a Drosophila model of CFL2 nemaline myopathy (5F30HD111309-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10829207. Licensed CC0.

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