# Systemic Integrative Mechanisms and Intervention Strategies in Exercise-Induced Skeletal Muscle Damage: Evidence from Animal, Clinical, and Multi-Omics Studies

## TL;DR

This paper explores how exercise-induced muscle damage involves complex interactions between mechanical stress, metabolism, and immunity, and how these systems can lead to injury or recovery.

## Contribution

The study introduces a systems biology framework for understanding exercise-induced muscle damage and evaluates interventions based on multi-omics and clinical evidence.

## Key findings

- EIMD involves feedback loops between mechanical, metabolic, oxidative, and immune processes.
- Molecular tipping points like ROS accumulation and iron-dependent lipid peroxidation determine injury outcomes.
- Satellite cells integrate metabolic history and epigenetic memory, affecting muscle adaptability and disease risk.

## Abstract

Exercise-induced muscle damage (EIMD) has classically been attributed to localized mechanical disruption following eccentric contractions. Emerging evidence, however, indicates that EIMD represents a systems-level failure of stress integration within skeletal muscle rather than a purely mechanical lesion. Mechanical loading initiates disturbances in intracellular Ca2+ homeostasis, which interact with metabolic stress, redox imbalance, and immune activation to form self-reinforcing feedback loops. When compensatory capacity is exceeded, transient injury may shift toward maladaptive remodeling marked by mitochondrial dysfunction, ferroptosis, chronic inflammation, and impaired regeneration. Recent studies identify reactive oxygen species accumulation, iron-dependent lipid peroxidation, dysregulated energy sensing, and aberrant immune polarization as key molecular tipping points governing injury reversibility. Beyond their regenerative role, satellite cells act as integrators of metabolic history and epigenetic memory, linking repetitive injury to reduced muscle adaptability, age-related sarcopenia, and heightened metabolic disease risk. Here, we synthesize evidence from animal models, clinical studies, and multi-omics analyses to establish a systems biology framework for EIMD. We delineate the spatiotemporal interactions among mechanical, metabolic, oxidative, immune, and regenerative modules; identify regulatory nodes that determine adaptive repair versus pathological outcomes; and critically evaluate current nutritional, physical, pharmacological, and regenerative interventions from a mechanism-oriented perspective. Finally, we discuss how multi-omics, digital monitoring, and individualized rehabilitation may enable precision management of EIMD and advance understanding of muscle stress resilience and adaptive limits.