Chemotherapy-Induced Skeletal Muscle Dysfunction and Cognitive Impairment: A Muscle-Brain Mechanistic Framework With Implications for Exercise Oncology.

Chemotherapy commonly induces skeletal muscle dysfunction and cognitive impairment, complications that reduce treatment tolerance and quality of life. Skeletal muscle mass frequently declines during chemotherapy, with cohort studies reporting losses of 3%-10% across treatment courses, while chemotherapy-induced cognitive impairment affects up to one-third of patients. Emerging evidence indicates that chemotherapeutic agents impair mitochondrial function in peripheral tissues, including skeletal muscle, increasing systemic oxidative stress and inflammatory cytokines. These factors may promote oxidative stress and inflammation within the brain, particularly in the hippocampus, contributing to neuronal mitochondrial dysfunction, apoptosis and cognitive decline. Skeletal muscle may therefore represent an important component within a broader muscle-brain axis linking chemotherapy-induced metabolic dysfunction with brain health. Targeted exercise improves skeletal muscle mitochondrial function, reduces systemic inflammation and oxidative stress and modulates multiple exercise-responsive signalling pathways, including myokines such as brain-derived neurotrophic factor and irisin. Collectively, these adaptations may contribute to improved neuronal health, neurogenesis and cognitive function. Understanding these interconnected mechanisms may inform exercise strategies to mitigate chemotherapy-related cognitive impairment.