Activation of the PI3K/Akt/FoxO pathway induces cell growth, while its inhibition reduces cell survival and in muscle, causes atrophy. During atrophy, plakoglobin is degraded by a mechanism involving the ubiquitin ligase, Trim32. Inhibition of Trim32 spares plakoglobin, which binds to the insulin receptor and the PI3K subunit, p85, and promotes PI3K/Akt/FoxO signaling. Trim32, by promoting plakoglobin loss, reduces PI3K/Akt/FoxO signaling in normal and atrophying muscle. Furthermore, Trim32 inhibition in normal muscle causes plakoglobin accumulation, increases PI3K/Akt/FoxO signaling, enhances glucose uptake, and induces fiber growth, while plakoglobin downregulation reduces PI3K/Akt/FoxO signaling, decreases glucose uptake, and causes atrophy. Thus, Trim32, by promoting plakoglobin loss, reduces PI3K/Akt/FoxO signaling in normal and atrophying muscle.
- Trim32 functions as a novel inhibitor of PI3K/Akt/FoxO signaling
- Trim32 promoting the degradation of plakoglobin, which is important for activation of this pathway in muscle and probably most tissues
- New diabetes or other metabolic diseases target
Applications and Opportunities
- Trim32 as a therapeutic target for muscle atrophy
- Trim32 as a drug target for treatment of diabetes, fasting and other catabolic conditions associated with insulin resistance and atrophy (sepsis, obesity)
- Trim32 inhibitors for therapeutic intervention