Trim32 reduces PI3K-Akt-Fox0 signaling in muscle atrophy by promoting plakoglobin-PI3K dissociation

Activation of the PI3K-Akt-Fox0 pathway induces cell growth, whereas its inhibition reduces cell survival and, in muscle, causes atrophy. Here, we report a novel mechanism that suppresses PI3K-Akt-Fox0 signaling. Although skeletal muscle lacks desmosomes, it contains multiple desmosomal components, including plakoglobin. In normal muscle plakoglobin binds the insulin receptor and PI3K subunit p85 and promotes PI3K-Akt-Fox0 signaling. During atrophy, however, its interaction with PI3K-p85 is reduced by the ubiquitin ligase Trim32 (tripartite motif containing protein 32). Inhibition of Trim32 enhanced plakoglobin binding to PI3K-p85 and promoted PI3K-Akt-Fox0 signaling. Surprisingly, plakoglobin overexpression alone enhanced PI3K-Akt-Fox0 signaling. Furthermore, Trim32 inhibition in normal muscle increased PI3K-Akt-Fox0 signaling, enhanced glucose uptake, and induced fiber growth, whereas plakoglobin down-regulation reduced PI3K-Akt-Fox0 signaling, decreased glucose uptake, and caused atrophy. Thus, by promoting plakoglobin PI3K dissociation, Trim32 reduces PI3K-Akt-Fox0 signaling in normal and atrophying muscle. This mechanism probably contributes to insulin resistance during fasting and catabolic diseases and perhaps to the myopathies and cardiomyopathies seen with Trim32 and plakoglobin mutations.