Activation of the Retinoid X Receptor Augments the Expression of Akt2 to Enhance Myogenic Differentiation

Abstract

Cachexia or muscle atrophy is a condition that is associated with a variety of diseases such as chronic heart failure and cancer. In North America, Europe and Japan, more than 8 million patients suffer from cachexia, and it is estimated that cachexia is the cause of death in 30% of cancer patients. Unfortunately, there is no available treatment for cachexia. Bexarotene, a retinoid X receptor (RXR) agonist, is a FDA approved drug used to treat cancer and is able to induce myogenic differentiation in embryonic stem cells. In this study, we investigated the mechanism by which bexarotene enhances myogenic differentiation. The Akt signaling pathway is required for myogenesis and thus we examined its involvement in bexarotene-enhanced myogenic differentiation. We showed that bexarotene, through the activation of RXR signaling, regulates Akt2 expression to enhance myoblast differentiation and fusion. Additionally, we showed that Akt2, but neither Akt1 nor Akt3, is required for bexarotene-enhanced differentiation. Furthermore, we showed that the activation of RXR signaling by bexarotene correlates with a specific histone acetylation mark at the Akt2 locus. More importantly, we demonstrated that bexarotene is able to rescue myoblast differentiation in an in vitro cachexia system. Taken together, our data revealed the significance of Akt2 in bexarotene-enhanced myogenic differentiation and the potential of using bexarotene as a treatment for cachexia.