Exercise-Induced Skeletal Muscle Mitochondrial Stress Mediates Systemic Health Adaptation via Cell-Nonautonomous Signaling

Regular physical activity confers systemic health protection extending beyond any single organ system. The recognition that contracting skeletal muscle releases myokines, metabolites, and extracellular vesicles established that muscle communicates with distal organs during exercise, yet this paradigm centers on acute metabolic homeostasis and does not fully explain how exercise builds lasting resilience against diseases that may not manifest for years. The concept of cell-nonautonomous mitochondrial stress signaling, first characterized in Caenorhabditis elegans , provides a framework for understanding how a localized mitochondrial perturbation can generate persistent systemic protection through spatially propagated, molecularly transmitted, and epigenetically retained signals. Exercise imposes transient sublethal mitochondrial stress on skeletal muscle, characterized by increased reactive oxygen species production and protein folding demands. This stress activates the mitochondrial integrated stress response and unfolded protein response, which regulate the synthesis and release of myokines (FGF21, GDF15, MOTS-c), metabolites (succinate, itaconate, BAIBA, β-hydroxybutyrate), and extracellular vesicles carrying mitochondrial material. These signals converge on mitochondrial quality control (MQC) pathways in the liver, heart, brain, and adipose tissue, enhancing respiratory capacity, antioxidant defenses, and mitophagy. The liver amplifies this network through systemic FGF21 and GDF15 secretion. Transient molecular messengers are converted into persistent epigenetic modifications via DNA methylation, histone modifications, and non-coding RNAs, enabling distal organs to maintain elevated mitochondrial stress resistance. This review synthesizes evidence that exercise-induced skeletal muscle mitochondrial stress serves as the initiating stimulus for systemic health adaptation through a multilayered cell-nonautonomous signaling program, and identifies key open questions regarding signal specificity, epigenetic durability, and dose-response relationships.