# Mechanistic study of skeletal muscle proteolysis induced by breast cancer-secreted extracellular vesicles

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $250,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Skeletal muscle loss and weakness are a key part of cancer cachexia and are associated with poor clinical
outcomes and a poor quality of life in cancer patients. Despite previous advances in understanding the
mechanisms of cancer cachexia, little is known about how the presence of breast cancer influences skeletal
muscle, and no early detection method or therapy currently exists for cancer-associated muscle loss and
cachexia. The proposed project will investigate this unique aspect of tumor–host crosstalk from the novel
perspective of cancer-secreted extracellular vesicles (EVs), whose function in transferring cancer-derived
signals to various types of normal cells has been recently recognized. The goal of this study is to identify
the mechanisms by which breast cancer-secreted EVs dysregulate skeletal muscle mass and function.
We will test the novel hypothesis that miRNA and protein cargo of cancer-secreted EVs induce muscle
protein degradation by activating the calcium-dependent calpain proteases and the ubiquitin-proteasome
system. In Aim 1, we will first determine how selected miRNA cargo of breast cancer-secreted EVs dysregulate
calcium transport in muscle cells to activate calpains and promote muscle protein breakdown. Using mouse
models, we will evaluate to what extent this mechanism contributes to cancer-associated muscle mass loss
and dysfunction. Next, we will identify the mechanism through which breast cancer-secreted EVs stimulate
macrophages to induce skeletal muscle inflammation and how this activates the ubiquitin-proteasome system
to promote protein degradation. The role of macrophages and inflammatory cytokines will be determined using
mouse models. In Aim 2, we will assess the beneficial effects of potential therapeutics targeting EV-mediated
mechanisms on skeletal muscle. Experimental therapeutic approaches will be assessed individually or in
combination in mouse models for the efficacy in protecting muscle from the devastating effect of selected EV
cargo effectors. The therapeutics will be administered before or after cancer-associated skeletal muscle loss is
detected, to assess their performance in the prevention and treatment settings. In Aim 3, we will analyze blood
samples and computed tomography scan images from breast cancer patients, to assess the associations
between selected EV cargo molecules and parameters of skeletal muscle loss. The proposed study will
provide a new understanding of the distant effects of cancer on skeletal muscle. It will also establish rationales
for novel therapeutic strategies to prevent or treat cancer-associated muscle loss and cachexia, which would
improve the quality of life in cancer patients by restoring muscle function and indirectly improve anticancer
treatment response towards our long-term objective to deliver better cancer care and achieve better results for
patients.

## Key facts

- **NIH application ID:** 10704327
- **Project number:** 1R56AR080153-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Simon Schenk
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $250,000
- **Award type:** 1
- **Project period:** 2022-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10704327

## Citation

> US National Institutes of Health, RePORTER application 10704327, Mechanistic study of skeletal muscle proteolysis induced by breast cancer-secreted extracellular vesicles (1R56AR080153-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10704327. Licensed CC0.

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