# Inhibition of TRPC3-Nox2 Complex Formation Ameliorates Skeletal Muscle Atrophy

## TL;DR

Blocking the TRPC3-Nox2 complex reduces skeletal muscle atrophy in mouse models of muscular dystrophy and nerve damage.

## Contribution

The study identifies TRPC3-Nox2 complex formation as a novel driver of oxidative stress-induced skeletal muscle atrophy.

## Key findings

- TRPC3-Nox2 complex formation is increased in denervated and dystrophic skeletal muscle.
- Pharmacological disruption of TRPC3-Nox2 reduces muscle atrophy and ROS production in mdx mice.
- AAV-mediated delivery of a TRPC3 C-terminal peptide mitigates muscle wasting in dystrophic mice.

## Abstract

Skeletal muscle atrophy underlies sarcopenia, frailty, and muscular dystrophies, but the molecular mechanisms linking oxidative stress to muscle degeneration remain incompletely understood. We previously identified protein complex formation between transient receptor potential canonical 3 (TRPC3) and NADPH oxidase 2 (Nox2) as a key driver of anthracycline-induced myocardial atrophy. Here, we investigated whether this complex also contributes to skeletal muscle wasting. In skeletal muscle from sciatic nerve transection model mice and Duchenne muscular dystrophy (mdx) mice, TRPC3-Nox2 complex formation was enhanced. TRPC3 deletion significantly attenuated denervation-induced soleus atrophy and reduced reactive oxygen species (ROS) production. TRPC3-Nox2 complex formation was upregulated in the soleus muscle (SM) of mdx mice. Pharmacological disruption of the TRPC3-Nox2 interaction improved muscle size and strength and reduced plasma creatine kinase in mdx mice. A recombinant adeno-associated virus (AAV) encoding a TRPC3 C-terminal peptide was used to suppress TRPC3-Nox2 complex formation in vivo. AAV-mediated expression of TRPC3 C-terminal peptide mitigated muscle wasting (CSA) in mdx mice, while muscle strength and plasma CK were not significantly improved. Thus, TRPC3-Nox2 complex formation may be a pivotal driver of oxidative stress-mediated skeletal muscle atrophy. Targeting this protein–protein interaction represents a promising therapeutic strategy for Duchenne muscular dystrophy (DMD) and other intractable muscle-wasting disorders.