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MITOCHONDRIAL QUALITY CONTROL MARKERS DURING THE ONSET OF COLORECTAL CANCER-INDUCED CACHEXIA: A BIOLOGICAL SEX COMPARISON

Abstract

Ana Regina Cabrera1, J. William Deaver1, Seongkyun Lim1, Francielly Morena da Silva1,

Eleanor R. Schrems1, Landen W. Saling1, Anthony Campitelli1, Tyrone A. Washington1, Nicholas P. Greene1.

1University of Arkansas, Fayetteville, Arkansas

Cancer cachexia (CC) represents 20-40% of mortality among cancer patients. It is characterized by involuntary weight loss despite nutritional interventions, affecting the quantity and quality of life of cancer-diagnosed patients without effective therapies available to treat it. Skeletal muscle (SM) is one of the primarily affected tissues in CC. Impaired mitochondria quality control markers (MQC), such as Opa1 and Bnip3, have been observed in other CC models, and are believed to play an important role initiating cancer-induced muscle loss. Moreover, evidence suggests biological sex differences in CC. The critical mechanisms of how this pathology evolves and how it affects muscle health in both males and females remain underexplored. PURPOSE: To investigate biological sex variation in MQC markers in muscle during the early development of colorectal CC. METHODS: Eight-week-old BALB/c mice (69 males, 60 females) were separated into five groups (PBS, 10-, 15-, 20-, and 25-day). Tumor bearing groups (TBG) of 10-25-day received C26 colorectal cancer cell injections at day 0, while control mice received PBS administration as vehicle control. Soleus (SOL), Gastrocnemius (GC), and Tibialis Anterior (TA) muscles were collected at each time point, and mRNA content of Opa1 and Bnip3 were measured. A one way-ANOVA across time points within each sex was performed as the global analysis with α=0.05. RESULTS: In SOL, lower Opa1 mRNA content (~49%, p<0.05) was seen in females of the 10-day TBG; and in TA (~29%, p<0.05) in the 25-day TBG in males. Differences against PBS group were absent in GC both sexes, SOL in males, and TA in females. Bnip3 mRNA content was higher in GC in males (~98%, p<0.05) in the 25-day TBG, while other tissues and females maintained relatively constant Bnip3 mRNA contents. CONCLUSION: Our results show biological sex response to CC, where females tend to better preserve their mitochondrial health during the developing of CC in different muscle types. In addition, the differences observed in the MQC of each muscle type within the same sex, is evidence of intrinsic muscle variations in mitochondrial metabolism changing during tumor development. This muscle heterogenicity and sex differences to CC demonstrate the importance of investigate for mechanisms related to muscle function and personalized therapies.

ACKNOWLEDGEMENTS: Funded by the NIH, Award: R01 AR075794-02.

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