["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend PoWeR training (11.5 weeks of voluntary wheel running with progressively increased resistance) before and during cancer attenuates muscle loss, limits tumour growth, drives a transition toward a more oxidative muscle phenotype (IIB‐to‐IIA shift), downregulates cachexia‐associated pathways and enhances mitochondrial performance in C26 tumour‐bearing mice. Created with BioRender.com.\n\n\n\n\n\n\n\n\n\nAbstract\nWe investigated the prophylactic effects of exercise before and during cancer cachexia (CC) using a model designed to mimic endurance and resistance (i.e., concurrent) adaptations. Male and female Balb/c mice were randomly assigned to exercise or control groups whereby exercise groups were subjected to an 8‐week voluntary progressive weighted wheel running (PoWeR) programme of habitual loading‐mediated physical activity beginning at 8 weeks of age. At 16 weeks of age, mice were injected bilaterally with colon‐26 adenocarcinoma (C26) cells or phosphate‐buffered saline, and exercise training was maintained throughout disease progression. Twenty‐five days post‐tumour induction, we assessed whole‐body and muscle phenotype, muscle protein synthesis, a priori targeted gene expression, and transcriptomic adaptations via RNA sequencing. PoWeR training preserved skeletal muscle mass across nearly all muscle groups and maintained tumour‐free body and cardiac mass. Muscle mass adaptations related to running volume, and running distance relative to controls were not appreciably reduced by tumour status. Tumour burden was reduced after ∼11.5 weeks of PoWeR compared to sedentary, but this was not explanatory for muscle adaptations. PoWeR induced a faster‐to‐slower muscle fibre type transition in the gastrocnemius and suppressed key protein turnover markers (Redd1, Murf1, Atrogin, Ubc, Gadd45a) as well as the mitophagy‐related marker Bnip3 in tumour‐bearing muscle; 24 h muscle protein synthesis remained stable. PoWeR counteracted tumour‐induced impairments in the muscle mitochondrial‐ and metabolic‐related transcriptome. Collectively, physical activity prior to and during cancer preserves muscle mass, reduces tumour growth and mitigates molecular drivers of CC, underscoring its preventive and therapeutic potential as a lifestyle intervention.\n\n\n\n\n\n\n\n\n\nKey points\n\nCancer cachexia (CC) is a severe, multifactorial syndrome with limited effective therapies.\nExercise training has emerged as a promising non‐pharmacological approach to mitigate CC.\nConcurrent endurance and resistance training, initiated prior to and maintained during cancer, preserves skeletal muscle mass and reduces tumour burden in C26 colorectal tumour‐bearing mice.\nConcurrent exercise training suppresses key mitochondrial‐ and metabolic‐related molecular mediators of CC.\nConcurrent exercise training may serve as a preventive and therapeutic non‐pharmacological strategy against CC.\n\n\n"]