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MyoD-dependent regulation of NF-κB activity couples cell-cycle withdrawal to myogenic differentiation

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Author(s): Parker Maura H | von Maltzahn Julia | Bakkar Nadine | Al-Joubori Ban | Ishibashi Jeff | Guttridge Denis | Rudnicki Michael A

Journal: Skeletal Muscle
ISSN 2044-5040

Volume: 2;
Issue: 1;
Start page: 6;
Date: 2012;
Original page

Keywords: Skeletal muscle | Myoblasts | MyoD | NF-κB | IKK | IκB | Differentiation | Myogenesis

ABSTRACT
Abstract Background Mice lacking MyoD exhibit delayed skeletal muscle regeneration and markedly enhanced numbers of satellite cells. Myoblasts isolated from MyoD-/- myoblasts proliferate more rapidly than wild type myoblasts, display a dramatic delay in differentiation, and continue to incorporate BrdU after serum withdrawal. Methods Primary myoblasts isolated from wild type and MyoD-/- mutant mice were examined by microarray analysis and further characterized by cell and molecular experiments in cell culture. Results We found that NF-κB, a key regulator of cell-cycle withdrawal and differentiation, aberrantly maintains nuclear localization and transcriptional activity in MyoD-/- 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 MyoD-/- 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. Conclusion 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.
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