Two tales concerning skeletal muscle
David J. Glass
David J. Glass
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2388-2391. https://doi.org/10.1172/JCI33379.
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Commentary

Two tales concerning skeletal muscle

Abstract

It was previously appreciated that the determination of skeletal muscle fiber type (fast or slow) could be regulated by class II histone deacetylases (HDACs), which function by inhibiting the transcription factor myocyte enhancer factor 2 (MEF2). In a report by Potthoff et al. in this issue of the JCI, it is further shown that HDACs are degraded via the ubiquitin/proteasome pathway, opening up a search for the putative E3 ligase that mediates the proteolysis of the responsible HDACs (see the related article beginning on page 2459). In a second report, by Suzuki et al., a new convergence between the biology of muscular dystrophy and muscle atrophy is elucidated (see the related study beginning on page 2468). It had previously been known that NO signaling is dysregulated during muscular dystrophy due to the disruption of the dystrophin glycoprotein complex (DGC), which anchors neuronal NOS (nNOS). Here it is shown that nNOS is similarly perturbed in a setting of skeletal muscle atrophy. Both of these studies suggest new avenues for the treatment of skeletal muscle disease.

Authors

David J. Glass

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Figure 2

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

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Dysregulation of nNOS from the sarcolemma: a new overlap in dystrophy/at...
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.