Investigating Differential StressResponse between the Extraocular and Tibialis Anterior Muscles under the Influence of Cancer Cachexia

Cancer cachexia, a debilitating syndrome causing muscle wasting, significantly affects cancer patients' survival and quality of life. This study investigates the differential response of extraocular muscles (EOMs) and tibialis anterior (TA) muscle to cancer cachexia, aiming to understand the molecular mechanisms underlying muscle wasting. Utilizing single-cell RNA sequencing, we analyzed muscle stem cells (MuSCs) and whole muscle fibers from a cachexia-induced model and control groups. The analysis revealed distinct molecular signatures and regulatory pathways associated with EOM and TA muscles in response to cachexia. Remarkably, TA muscle showed significant atrophy induction, while EOM remained largely unaffected. Furthermore, we observed metabolic shutdown in TA muscle, accompanied by a shift towards fatty acid catabolism. MuSC analysis confirmed downregulation of quiescence markers and the Notch pathway specifically in cachexia, suggesting altered MuSC activation dynamics. Additionally, both muscle groups exhibited deregulation of extracellular matrix organization. These findings highlight the different susceptibilities of muscle groups to cancer cachexia and provide insights into the molecular mechanisms driving their differential responses. The spared status of EOMs in cachexia, along with the unique alterations in metabolic pathways and dynamics of Myonuclei and MuSCs, contributes to a deeper understanding of EOMs' properties and the underlying pathogenesis of cancer cachexia