Sex-divergent skeletal muscle remodeling emerges early in cancer cachexia.

Cancer cachexia is characterized by progressive skeletal muscle wasting and dysfunction, yet the early events that precede overt muscle wasting remain poorly defined. Here, we utilized a time-coursed C26 carcinoma model in male and female mice to define the precachectic 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 before 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 precachectic 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, whereas 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 precachectic windows that may guide early biomarker discovery and therapeutic strategies aimed at preventing progression and improving quality of life in patients with cancer.NEW & NOTEWORTHY By modeling cancer-associated cachexia over a time-course in male and female mice, we show that skeletal muscle remodeling begins before overt wasting is evident. The precachectic interval is marked by suppressed protein synthesis, muscle-local immune remodeling, extracellular matrix disruption, and metabolic vulnerability, with several responses differing by sex. These findings suggest that key features of cachexia emerge early in the disease time-course and may inform clinical approaches for detecting disease before significant muscle wasting occurs.