Sex Differences in Cancer Cachexia and a Novel Mitochondrial Target for Cancer-Induced Muscle Wasting

Cancer cachexia (CC) is a devastating wasting syndrome characterized by marked weight loss including skeletal muscle atrophy that affects approximately 80% of cancer patients. Current therapeutic treatments including pharmacological and nutritional intervention are insufficient to prevent or reverse it. Prior studies demonstrated lower muscle mass, impaired muscle function, and mitochondrial health in the development of CC. Specifically, mitochondrial fusion protein, Optic atrophy 1 (OPA1) which plays a significant role in skeletal muscle health, is suppressed in the development of CC. Furthermore, most pre-clinical CC studies were mainly focused on males although there are distinct phenotypical differences in skeletal muscle between males and females. Therefore, these studies were set to investigate two independent research questions (Chapter 3 & 4). The purpose of this dissertation project was to investigate skeletal muscle alterations during the development of CC in female tumor-bearing mice (Chapter 3) and determine the efficacy of OPA1 as a therapeutic target for cancer-induced muscle atrophy (Chapter 4). To accomplish this research plan, I completed a series of studies using both cell culture and animal models of CC. For the Chapter 3 experiments, 60 female mice were given either an IP injection of PBS or Lewis Lung Carcinoma (LLC) injection and the tumors were allowed to grow for 1, 2, 3, or 4-wk to assess the time course of cachectic development. We found a dichotomous effect on tumor mass between 3- and 4-wk animals where approximately half of mice between the two groups exhibited low tumor (LT) mass (\u3c1.2 g) while the other half developed higher tumor (HT) mass (\u3e2 g). Furthermore, HT mice revealed greater protein degradation, impaired muscle contractility, and mitochondrial degeneration. These alterations are relatively modest when compared to male data from previous studies. For the Chapter 4 experiments, I utilized both pharmacological (in vitro & in vivo) and genetic overexpression of OPA1 (OPA1 TG) in LLC-conditioned media (LCM) and LLC-induced CC. 72 hours of LCM intervention induced smaller myotubes, which was normalized by BGP-15 treatment and this effect appeared to be driven by suppressed inflammatory cytokine and autophagic-lysosomal pathway (ALP) activity at the mRNA level. 4-wk of LLC implantation was sufficient to induce cachectic phenotype while this effect was normalized in OPA1 overexpression in tumor-bearing mice. In conclusion, my dissertation data suggests both biological sex as an important variable and OPA1 as a novel therapeutic target for cancer-induced muscle wasting