A Transcriptomic Analysis of the Development of Skeletal Muscle Atrophy in Cancer-Cachexia in Tumor-Bearing Mice.

Cancer-Cachexia (CC) is a wasting condition directly responsible for 20-40% of cancer-related deaths. The mechanisms controlling development of CC-induced muscle wasting are not fully elucidated. Most investigations focus on the post-cachectic state and do not examine progression of the condition. We recently demonstrated mitochondrial degenerations precede muscle wasting in time course progression of CC. However, the extent of muscle perturbations prior to wasting in CC is unknown. Therefore, we performed global gene expression analysis in CC-induced muscle wasting to enhance understanding of intramuscular perturbations across the development of CC. Lewis Lung Carcinoma (LLC) was injected into the hind-flank of C57BL6/J mice at 8 wks age with tumor allowed to develop for 1, 2, 3, or 4 wks and compared to PBS injected control. Muscle wasting was evident at 4 wks LLC. RNA sequencing of gastrocnemius muscle samples showed widespread alterations in LLC compared to PBS animals with largest differences seen in 4 wk LLC suggesting extensive transcriptomic alterations concurrent to muscle wasting. Commonly altered pathways included: Mitochondrial Dysfunction and Protein Ubiquitination, along with other less studied processes in this condition regulating transcription/translation and cytoskeletal structure. Current findings present novel evidence of transcriptomic shifts and altered cellular pathways in CC-induced muscle wasting.