Trim32 as a therapeutic target for muscle atrophy

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Pharmaceuticals and Biotechnology

The Technology

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.

Advantages

  • 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
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Dr. Gal Gur
Director of Business Development, Life Sciences