# Skeletal muscle reprogramming in peripheral nerve injury: mechanisms, therapeutic roles, and complication management

## TL;DR

This paper reviews how reprogramming skeletal muscle can help repair nerve injuries by targeting muscle cells and their environment to improve recovery and reduce complications.

## Contribution

The paper introduces skeletal muscle reprogramming as a novel therapeutic strategy for peripheral nerve injury, highlighting its potential to enhance regeneration and functional recovery.

## Key findings

- Skeletal muscle reprogramming can reduce atrophy and fibrosis after nerve injury.
- Reprogramming strategies promote neuromuscular junction reconstruction and nerve regrowth.
- Key pathways like Wnt/β-catenin and TGF-β are involved in reprogramming effects.

## Abstract

Peripheral nerve injury (PNI) presents a significant clinical challenge, frequently leading to long-term neuromuscular dysfunction, muscle atrophy, fibrosis, and chronic pain. Traditional repair strategies, including microsurgical reconnection and neurotrophic support, often yield limited functional recovery, especially in cases of delayed or incomplete reinnervation. In this context, skeletal muscle reprogramming—defined as the intentional modulation of cellular fate, function, or metabolic state in muscle-resident cells—has emerged as a promising strategy to enhance regenerative outcomes. This process involves transcriptional, epigenetic, and metabolic interventions targeting myogenic progenitors, fibro-adipogenic progenitors (FAPs), satellite cells (MuSCs), and the broader muscle microenvironment. Recent studies demonstrate that reprogramming strategies can mitigate denervation-induced muscle atrophy, delay fibrotic remodeling, promote neuromuscular junction (NMJ) reconstruction, and even stimulate endogenous nerve regrowth via retrograde signaling. Mechanistic insights have uncovered pivotal roles for signaling pathways such as Wnt/β-catenin, TGF-β, Notch, and HDAC-regulated chromatin dynamics. Furthermore, innovations in small molecule cocktails, CRISPR-based transcriptional reactivation, and metabolic rewiring have expanded the therapeutic toolkit for muscle preservation and regeneration. This review comprehensively examines the molecular mechanisms, therapeutic roles, and translational challenges of skeletal muscle reprogramming in the context of PNI. We explore how muscle-targeted interventions can address complications of denervation, improve the efficacy of nerve repair, and offer a synergistic axis of regeneration when integrated with nerve-centric strategies. Finally, we identify key knowledge gaps and outline future research directions required to translate reprogramming-based therapies into clinical practice.