Background: Cancer patients experience cachexia which is characterized by extensive skeletal muscle wasting that worsens the quality of life and increases mortality. However, there are no approved treatments that can effectively counteract cancer cachexia. Prior research has focused on the changes within the muscle tissue but little is known about the role of the muscle vasculature in mediating cancer cachexia. Vascular endothelial cells (ECs) are essential for maintaining tissue perfusion, nutrient supply and preventing inappropriate transmigration of immune cells into the tissue. We therefore hypothesized that endothelial dysfunction in the skeletal muscle results in the development of cachexia in cancer. The transcriptional co-activator PGC1α (peroxisome proliferation activator receptor-γ coactivator1-α) regulates endothelial health.

Methods and Results: To evaluate whether skeletal muscle EC-PGC1α is modulated in the setting of malignancy, we isolated muscle ECs from control and melanoma bearing mice at 1, 2, and 3 weeks after melanoma implantation. PGC1α expression was significantly decreased in mECs of melanoma bearing mice from early stage (1 week) compared with control mice. Thus, we generated an EC-specific inducible PGC1α deletion mouse model (ECΔPGC1α) to investigate the mechanistic role of EC-PGC1α in cancer cachexia in vivo. Interestingly, vascular density and muscle area were significantly decreased in the gastrocnemius (GC) of ECΔPGC1α mice compared with ECWT mice using an innovative tissue clearing and high-resolution 3D-tissue imaging system. Tumor bearing ECWT mice had decreased GC mass and weight compared with no tumor mice by enhancing cachexia marker genes, MuRF1 and Atrogin1. The tumor bearing ECΔPGC1α mice had further decreased muscle mass and weight, and grip strength than tumor bearing ECWT mice. We assessed the role of EC-PGC1α in the regulation of capillary function in vivo, and observed that ECΔPGC1α mice demonstrated significantly greater vascular leak than ECWT mice.

Conclusion: These data suggest that the presence of melanoma suppresses PGC1α expression in the skeletal muscle endothelium. Endothelial PGC1α, in turn, is essential for maintaining the integrity of the skeletal muscle vascular barrier. Our study suggests that restoring muscle endothelial dysfunction could be a novel therapeutic approach to prevent or reverse cancer cachexia.

Citation Format: Young-Mee Kim, Georgina Mancinelli, Paul Grippo, Jalees Rehman. Cancer cachexia is mediated by the suppression of PGC1-alpha expression in the skeletal muscle vasculature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2595.