Exercise training prior to and during cancer in mice preserves muscle mass, reduces tumour weight and suppresses molecular mediators of cachexia

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We 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. KEY POINTS: Cancer cachexia (CC) is a severe, multifactorial syndrome with limited effective therapies. Exercise training has emerged as a promising non-pharmacological approach to mitigate CC. Concurrent 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. Concurrent exercise training suppresses key mitochondrial- and metabolic-related molecular mediators of CC. Concurrent exercise training may serve as a preventive and therapeutic non-pharmacological strategy against CC.

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