| Summary: | <p>Abstract</p> <p>Background</p> <p>Mice lacking MyoD exhibit delayed skeletal muscle regeneration and markedly enhanced numbers of satellite cells. Myoblasts isolated from <it>MyoD</it><sup><it>-/-</it></sup> myoblasts proliferate more rapidly than wild type myoblasts, display a dramatic delay in differentiation, and continue to incorporate BrdU after serum withdrawal.</p> <p>Methods</p> <p>Primary myoblasts isolated from wild type and <it>MyoD</it><sup><it>-/-</it></sup> mutant mice were examined by microarray analysis and further characterized by cell and molecular experiments in cell culture.</p> <p>Results</p> <p>We found that NF-κB, a key regulator of cell-cycle withdrawal and differentiation, aberrantly maintains nuclear localization and transcriptional activity in <it>MyoD</it><sup><it>-/-</it></sup> myoblasts. As a result, expression of cyclin D is maintained during serum withdrawal, inhibiting expression of muscle-specific genes and progression through the differentiation program. Sustained nuclear localization of cyclin E, and a concomitant increase in cdk2 activity maintains S-phase entry in <it>MyoD</it><sup><it>-/-</it></sup> myoblasts even in the absence of mitogens. Importantly, this deficit was rescued by forced expression of IκBαSR, a non-degradable mutant of IκBα, indicating that inhibition of NF-κB is sufficient to induce terminal myogenic differentiation in the absence of MyoD.</p> <p>Conclusion</p> <p>MyoD-induced cytoplasmic relocalization of NF-κB is an essential step in linking cell-cycle withdrawal to the terminal differentiation of skeletal myoblasts. These results provide important insight into the unique functions of MyoD in regulating the switch from progenitor proliferation to terminal differentiation.</p>
|
|---|