# SWELL1-LRRC8 mediated regulation of skeletal muscle function and metabolism

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $437,831

## Abstract

Project Summary
Maintenance of muscle mass is known to be beneficial in the prevention of obesity and obesity-related diseases
such as diabetes and heart disease, in addition to promoting overall health of our aging population. Skeletal
muscle atrophy is associated with cancer (cachexia), heart failure, chronic corticosteroid use, paralysis or
denervation (disuse atrophy), aging, contributing to poor metabolic health, and increased mortality. Accordingly,
a deeper understanding of the molecular mechanisms that regulate skeletal muscle maintenance, growth and
function is critical for human health.
We recently showed that, in skeletal muscle, SWELL1 is required for maintaining AKT-mTOR signaling, normal
muscle fiber size, exercise capacity, force generation, adiposity and systemic glycemia, thereby revealing a novel
role for a SWELL1-AKT-mTOR signaling axis in skeletal muscle physiology. Furthermore, our group now has
published and unpublished biochemical, patch-clamp and imaging evidence that SWELL1 channel
complexes are also expressed and functional in lysosomes (Lyso-SWELL1) – a notion also supported
by a recent unbiased CRISPR screen. Given that lysosomes are signaling hubs that integrate nutrient sensing
and AKT-mTOR signaling, we hypothesize that SWELL1-LRRC8 channels co-regulate plasma membrane
PI3K-AKT signaling and lysosome centered nutrient-mTOR signaling. To test this hypothesis, we combine
our unique reagents and expertise in SWELL1 signaling with the those of the Diwan (lysosomal signaling), Xu
(lysosomal patch-clamp), and Meyer (skeletal muscle physiology) laboratories. Our objective is to understand
the dual mechanisms of plasma membrane SWELL1 signaling and lysosomal SWELL1 (Lyso-SWELL1) nutrient
sensing in skeletal muscle and its contribution to skeletal muscle growth and function. The rationale for these
studies is that delineating the molecular mechanisms of skeletal muscle SWELL1-AKT-mTOR signaling will
advance our understanding of novel, fundamental mechano-signaling and nutrient sensing mechanisms that
regulate skeletal muscle growth and function. We propose the following AIMs:
· AIM#1: Delineate the mechanisms of plasma membrane versus lysosomal SWELL1 signaling to AKT-
 mTOR signaling in skeletal muscle cells. These studies will test a novel paradigm for cellular nutrient sensing
 by a lysosomal ion channel signaling complex in vitro, setting the stage for in vivo experiments.
· AIM#2: Examine the contribution of SWELL1 signaling to aerobic capacity, skeletal muscle growth, and
 force generation in vivo with training and with aging. These studies will define the contributions of SWELL1
 signaling to skeletal muscle growth and signaling in vivo, and with aging.

## Key facts

- **NIH application ID:** 10305237
- **Project number:** 1R01DK127080-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Rajan Sah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $437,831
- **Award type:** 1
- **Project period:** 2021-07-20 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10305237

## Citation

> US National Institutes of Health, RePORTER application 10305237, SWELL1-LRRC8 mediated regulation of skeletal muscle function and metabolism (1R01DK127080-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10305237. Licensed CC0.

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