Dr. Imed Gallouzi - Department of Biochemistry
The role of RNA Binding proteins in the onset of cancer-induced cachexia: new potential avenue for therapy
Pro-inflammatory diseases, such as cancer, AIDS, and COPD, are often associated with a progressive loss of skeletal muscle tissue, a syndrome also known as cachexia. It is known that pro-inflammatory cytokines, such as TNFa and IFNg, trigger muscle loss by activating downstream inflammatory pathways. In this seminar I will present evidence supporting the idea that RNA binding proteins, such as HuR and the mRNA decay factor KSRP play a key role in the onset of this deadly syndrome. Under cachectic conditions, HuR switches its function from a promoter of muscle fiber formation to become an inducer of muscle loss. HuR binds to the STAT3 mRNA, which encodes one of the main effectors of this condition, promoting its expression both in vitro and in vivo. While HuR does not affect the stability and the cellular movement of this transcript, HuR promotes the translation of the STAT3 mRNA by preventing miR-330-mediated translation inhibition. To achieve this effect, HuR directly binds to a U-rich element in the STAT3 mRNA-3’untranslated region (UTR) located within the vicinity of the miR-330 seed element. We next investigated the in vivo role of HuR in muscle physiology and disease-induced atrophy. We observed that that muscle-specific HuR knockout (muHuR-KO) mice have high exercise endurance that is associated with enhanced oxygen consumption and carbon dioxide production. muHuR-KO mice exhibit a significant increase in the proportion of oxidative type I fibers in several skeletal muscles. HuR mediates these effects by collaborating with the mRNA decay factor KSRP to destabilize the PGC-1α mRNA. The type I fiber-enriched phenotype of muHuR-KO mice protects against cancer cachexia-induced muscle loss. Therefore, our studies demonstrate the role of HuR in the onset of cancer-induced muscle wasting and provide a proof-of-principle that HuR expression can be targeted therapeutically in skeletal muscles to combat this deadly condition.