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. 2007 Sep 4;117(9):2388–2391. doi: 10.1172/JCI33379

Figure 2. Dysregulation of nNOS from the sarcolemma: a new overlap in dystrophy/atrophy signaling.

Figure 2

In the setting of muscle atrophy, nNOS activates FoxO, which is required for upregulation of the E3 ligases MuRF-1 and MAFbx. These E3s in part mediate the increase in protein turnover seen during muscle atrophy. IGF1 was previously shown to be able to block MuRF-1 and MAFbx upregulation by activating the Akt pathway. Akt phosphorylates the FoxO transcription factors, keeping them out of the nucleus. nNOS might act by inhibiting Akt signaling, thus allowing FoxO transcription factors to traffic to the nucleus. Alternatively, nNOS could act directly on FoxO proteins or via an undiscovered mechanism to activate the FoxO-induced muscle atrophy program. In this issue of the JCI, Suzuki et al. (16) demonstrate that nNOS is dysregulated, departing from DGC and resulting in the activation of FoxO transcription. IKK, inducible IκB kinase.