# Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline

## TL;DR

This review explores how physical activity can reduce ER stress in skeletal muscle, potentially improving muscle health in neurodegenerative diseases.

## Contribution

The paper highlights exercise as a novel strategy to combat muscle decline through modulation of ER stress and UPR pathways.

## Key findings

- Exercise enhances the adaptive UPR, reducing protein misfolding in muscle cells.
- Physical activity activates stress-resilience pathways and autophagy to mitigate ER stress.
- Exercise may improve muscle function and reduce wasting in diseases like ALS, PD, and AD.

## Abstract

The pathophysiology of neurodegenerative diseases is largely driven by ER stress, contributing to cellular dysfunction and inflammation. Chronic ER stress in skeletal muscle is associated with a deterioration in muscle function, particularly in diseases such as ALS, PD, and AD, which are often accompanied by muscle wasting and weakness. ER stress triggers the UPR, a cellular process designed to restore protein homeostasis, but prolonged or unresolved stress can lead to muscle degeneration. Recent studies indicate that exercise may modulate ER stress, thereby improving muscle health through the enhancement of the adaptive UPR, reducing protein misfolding, and promoting cellular repair mechanisms. This review examines the influence of exercise on the modulation of ER stress in muscle cells, with a particular focus on how physical activity influences key pathways contributed to mitochondrial function, protein folding, and quality control. We discuss how exercise-induced adaptations, including the activation of stress-resilience pathways, antioxidant responses, and autophagy, can help mitigate the negative effects of ER stress in muscle cells. Moreover, we examine the potential therapeutic implications of exercise in neurodegenerative diseases, where it may improve muscle function, reduce muscle wasting, and alleviate symptoms associated with ER stress. By integrating findings from neurobiology, muscle physiology, and cellular stress responses, this article highlights the therapeutic potential of exercise as a strategy to modulate ER stress and improve muscle function in neurodegenerative diseases.