Exercise Training Prior To and During Cancer in Mice Preserves Muscle Mass, Reduces Tumor Weight, and Suppresses Molecular Mediators of Cachexia

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) program 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 PBS, and exercise training was maintained throughout disease progression. Twenty-five days post-tumor 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 tumor-free body and cardiac mass. Muscle mass adaptations related to running volume; and running distance relative to controls was not appreciably reduced by tumor status. Tumor 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 fiber 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 tumor-bearing muscle; 24h muscle protein synthesis remained stable. PoWeR counteracted tumor-induced impairments in the muscle mitochondrial- and metabolic-related transcriptome. Collectively, physical activity prior to and during cancer preserves muscle mass, reduces tumor growth, and mitigates molecular drivers of CC, underscoring its preventive and therapeutic potential as a lifestyle intervention.