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 1

Ubiquitination of class II HDACs causes their degradation via the proteasome, allowing MEF2 to induce a slow–muscle fiber phenotype.

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Ubiquitination of class II HDACs causes their degradation via the protea...
One potential mechanism for regulation of HDAC sensitivity to ubiquitination is illustrated — SUMOylation. One model for MEF2 inactivation is that SUMOylated HDAC, which is associated with the SUMO E2, Ubc9, can associate with MEF2, leading to MEF2 SUMOylation and inactivation. In this issue of the JCI, Potthoff et al. (2) demonstrate that HDACs are degraded via ubiquitination in slow muscle fibers, resulting in active MEF2, which is necessary and sufficient to induce the expression of genes required for the slow–muscle fiber–type transcriptional program. Phosphorylation of the HDACs by CaMK (or dephosphorylation by calcineurin) does not seem, by itself, to perturb the sensitivity of HDAC to ubiquitination, but these proteins regulate HDAC localization to the nucleus; ubiquitinated HDAC proteins are found primarily in the nucleus, perhaps implicating a nuclear-localized E3 ubiquitin ligase. Ub, ubiquitin.