Sex-divergent skeletal muscle remodeling emerges early in cancer cachexia.
Cancer cachexia is characterised by progressive skeletal muscle wasting and dysfunction, yet the early events that precede overt muscle wasting remain poorly defined. Here, we utilised a time-coursed C26 carcinoma model in male and female mice to define the pre-cachectic transcriptomic, proteostatic, immune, and metabolic adaptations between sexes. Males progressed more rapidly to cachexia and exhibited earlier impairments in body composition and grip strength, with shifts in muscle fiber size distribution detectable prior to changes in muscle mass. Transcriptomic analysis of the tibialis anterior muscle identified >6,000 differentially expressed genes, with >60% showing sex-specific regulation at the pre-cachectic stage. Proteostasis pathways were transcriptionally altered in both sexes, however, global muscle protein synthesis was suppressed earlier in males, preceding both measurable muscle mass loss and robust induction of specific E3 ubiquitin ligases. Transcripts related to innate immunity were preferentially elevated in males and accompanied by increased infiltration of myeloid cells, while systemic immune profiles showed limited concordant changes. Females showed preferential enrichment of insulin resistance and metabolic remodeling pathways, accompanied by early impairment of insulin handling and reduced muscle glycogen content at severe cachexia. These results show that cachexia progression in this model is sexually dimorphic and skeletal muscle undergoes extensive remodeling before overt wasting. Males exhibit earlier functional decline and muscle immune remodeling, whereas females show earlier metabolic vulnerability with impaired insulin handling. These findings define sex-divergent pre-cachectic windows that may guide early biomarker discovery and therapeutic strategies aimed at preventing progression and improving quality of life in cancer patients.