# Neuromuscular Mechanisms and Oxidative Stress in Skeletal Muscle Atrophy: Emerging Stem Cell and Gene-Based Therapeutic Strategies

## TL;DR

This paper explores how muscle atrophy is caused by neuromuscular and metabolic issues and reviews new stem cell and gene-based treatments to address these problems.

## Contribution

The paper integrates recent findings on neuromuscular redox mechanisms and proposes novel therapeutic strategies for muscle atrophy.

## Key findings

- RONS activate pathways that accelerate muscle degradation through proteasome and autophagy lysosome systems.
- Stem cell therapies face challenges in engraftment and reinnervation despite their regenerative potential.
- Gene-based interventions and bioengineering platforms offer new treatment avenues but require overcoming safety and delivery barriers.

## Abstract

Skeletal muscle atrophy emerges from intertwined neuromuscular and metabolic failures, in which neuromuscular junction destabilization, excitation contraction coupling defects, and mitochondrial dysfunction collectively intensify calcium dysregulation and drive the accumulation of reactive oxygen and nitrogen species (RONS), reinforcing proteolytic and catabolic signaling programs. To integrate recent evidence on the neuromuscular redox interface and highlight therapeutic strategies that target these interdependent drivers of atrophy. RONS-mediated activation of NF-κB and FOXO pathways accelerates ubiquitin proteasome and autophagy lysosome degradation, leading to motor unit loss. Stem cell therapies (satellite cells, MSCs, and iPSC progenitors) seek to restore regenerative potential but face hurdles in engraftment and reinnervation. Gene-based interventions, including antioxidant gene delivery, Nrf2 activation, RNA modulators, and CRISPR editing, offer new avenues but remain limited by safety and delivery barriers. Bioengineering platforms such as hydrogels, decellularized scaffolds, and extracellular vesicles provide architectural, trophic, and immunomodulatory support. Translational progress requires rigorous safety pipelines, mechanistic biomarkers of motor unit recovery, and modular combination regimens that integrate cells, genes, scaffolds, and rehabilitative input. By aligning neuromuscular biology with redox control, emerging strategies hold promise to rebuild innervated, fatigue-resistant muscle across acquired and genetic atrophy syndromes.