45 | Interleukin-4 prevents cancer-induced muscle wasting and promotes exercise-like metabolic adaptations

Giacomo Rubini¹, E. E. Cappellato¹, L. C. Botinas¹, S. Reano², N. Filigheddu², A. Bonetto³, F. Penna¹, P. Costelli ¹ | ¹Dept. of Clinical and Biological Sciences, University of Turin, Italy; ²Dept. of Translational Medicine, University of Piemonte Orientale, Italy; ³Dept. of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Cancer cachexia is a complex syndrome characterized by body weight loss, muscle wasting, mitochondrial abnormalities and energy metabolism alterations. Previous findings showed that treating tumor-bearing (TB) mice with interleukin-4 (IL4) improved muscle fitness and myogenesis. IL4 and IL4 receptor were also found to be upregulated in the skeletal muscle after exercise. The present study aimed to investigate whether IL4 administration improves skeletal muscle energy metabolism in cancer hosts. Ten-weeks-old Balb/c male mice were inoculated with 5x10⁵ C26 colon carcinoma cells and sacrificed at days 10 or 15. Daily IL4 treatment (66.5 μg/kg) was performed by intraperitoneal injection. The gastrocnemius muscle was used to assess mitochondrial proteins (western blot) and respiration (high-resolution respirometry, Oroboros Instruments), and to perform metabolomic and lipidomic profiling (HPLC-coupled mass spectrometry). Treatment with IL4 prevented loss of body weight, muscle mass and muscle strength in day 15 TB mice. The protein levels of OXPHOS complexes II and III, cytochrome c and PGC-1α in the skeletal muscle were significantly increased in treated vs untreated TB mice. Similar trends were found for TOMM20, while trends to decrease were found for BNIP3. OXPHOS complex II activity was significantly increased in treated vs untreated TB mice. Tumor- and IL4-driven modulations in skeletal muscle metabolomic profile were observed, involving many energy-associated metabolites. Similarly, the skeletal muscle lipidome was altered by tumor burden and was partially restored by IL4. IL4 treatment improves energy metabolism in the skeletal muscle of TB mice. This effect relies on the improvement of mitochondrial homeostasis and the increased availability and capacity of mitochondrial OXPHOS complexes, suggesting that IL4 may act as an exercise mimetic. Further efforts to unravel the mechanism underlying IL4 efficacy are required.