The regulation of cancer cachexia and colorectal carcinogenesis by myostatin

Myostatin is a TGF-β superfamily member growth factor that regulates skeletal muscle mass and function. Although myostatin over-expression is associated with cancer-induced skeletal muscle wasting, also termed cancer cachexia, it is currently unknown whether this increase in myostatin levels can regulate tumorigenesis. We used the ApcMin/+ mouse to address this question. The ApcMin/+ mouse spontaneously develops multiple adenomas along the intestine. Using this model of intestinal tumorigenesis, we have demonstrated that the skeletal muscles of cachectic male ApcMin/+ mice express augmented amounts of myostatin mRNA. The inoculation of sActRIIB, an inhibitor of myostatin, partially prevented the loss of skeletal muscle mass and slightly improved the grip strength of cachectic ApcMin/+ mice when compared to dialysis buffer treated controls. In addition, the genetic inactivation of myostatin in the ApcMin/+ mouse (Mstn-/-::ApcMin/+) delayed the symptoms of cancer cachexia, thus establishing myostatin as a potential modulator of muscle wasting. The intestinal tumor number in the Mstn-/-::ApcMin/+ mouse displayed no difference to the wild type control (Mstn+/+::ApcMin/+). We next employed the AOM/DSS model of colorectal carcinogenesis to query the link between myostatin and intestinal carcinogenesis. The AOM/DSS model is a multistep chemical carcinogenesis protocol that induces the formation of several tumors in the colon. Unlike wild type Mstn+/+ mice, Mstn-/- mice were resistant to AOM/DSS mediated colorectal carcinogenesis, as myostatin deficient mice demonstrated an approximately 75% reduction in the incidence of colonic tumors when compared to the wild type control. The findings in this thesis raise an argument for the development of therapeutics that block the function of myostatin to ameliorate cancer cachexia. Due to the disparity in the extent of colorectal tumorigenesis between the ApcMin/+ and AOM/DSS models, however, it is premature to suggest a definitive link between myostatin and intestinal tumorigenesis.​Doctor of Philosophy (SBS