title: MyoD-dependent regulation of NF-κB activity couples cell-cycle withdrawal to myogenic differentiation.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Ottawa Hospital Research Institute, 501 Smyth Rd, Ottawa, ON, K1H 8L6, Canada. mrudnicki@ohri.ca.
authors.forename: Maura H
authors.initials: MH
authors.lastname: Parker
authors.forename: Julia
authors.initials: J
authors.lastname: von Maltzahn
authors.forename: Nadine
authors.initials: N
authors.lastname: Bakkar
authors.forename: Ban
authors.initials: B
authors.lastname: Al-Joubori
authors.forename: Jeff
authors.initials: J
authors.lastname: Ishibashi
authors.forename: Denis
authors.initials: D
authors.lastname: Guttridge
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rudnicki