Biological Sex Mediates Cancer Cachexia Muscle Autophagy

Abstract

Cancer cachexia, a catastrophic wasting disorder which affects roughly 80 percent of cancer patients, is characterized by the excessive catabolism of fat and muscle for energy. Unfortunately, cancer cachexia can cause irreversible damage to the body, decrease survival rate, and cause significant decline in quality of life. Therefore a great need exists to better understand the underlying mechanisms of cancer cachexia. Emerging evidence indicates that cancer cachexia also presents in a sexually dimorphic manner. Therefore, the purpose of this study was to determine the underlying mechanisms of sex-mediated mechanisms in cancer cachexia. Male and female LC3 Tg+ mice and sibling-matched wildtype mice implanted with tumors (T; 1x106 LLC cells in flank) or remained non-tumor (NT) for 3 weeks. In this dual tagged LC3 Tg+ autophagy reporter mouse model, early phase autophagosomes appear yellow (GFP+RFP) while late phase autolysosomes appear red (RFP only. Confocal analysis revealed that tumor bearing (T) resulted in a significant increase in late phase autolysosomes in the hearts of both sexes compared to NT hearts (P<0.05). However, males T hearts exhibited significantly greater early phase autolysosomes compared to female T hearts (P<0.001), while female T hearts exhibited significantly greater late phase autolysosomes compared to male T hearts (P<0.05). This coincided with increased inflammatory protein IL-1beta in female T hearts compared to female NT hearts (P<0.05). In skeletal muscle, tumor bearing led to significant increases in both early and late phase phagosomes in both sexes compared to NT skeletal muscles (P<0.05). However, female T skeletal muscle exhibited significantly greater early phase autophagosomes compared to male T muscles (P<0.05), while male T muscle exhibited significantly greater late phase autolysosomes compared to female T muscles (P<0.05). Interestingly, this coincided with increased inflammatory proteins IL-1beta (P<0.01) and NF-kB (P<0.05) in male T skeletal muscle compared to male NT muscle. Therefore, it is possible that inflammatory pathways mediate cancer cachexia associated autophagy in a sexually dimorphic manner. Such data are critical in elucidating how cancer cachexia variably presents and progresses by biological sex, and in the identification of therapeutic targets aimed at muscle wasting in a sex specific manner.