MyoD- and nerve-dependent maintenance of MyoD expression in mature muscle fibres acts through the DRR/PRR element.
BACKGROUND
MyoD is a transcription factor implicated in the regulation of adult muscle gene expression. Distinguishing the expression of MyoD in satellite myoblasts and muscle fibres has proved difficult in vivo leading to controversy over the significance of MyoD expression within adult innervated muscle fibres. Here we employ the MD6.0-lacZ transgenic mouse, in which the 6 kb proximal enhancer/promoter (DRR/PRR) of MyoD drives lacZ, to show that MyoD is present and transcriptionally active in many adult muscle fibres.


RESULTS
In culture, MD6.0-lacZ expresses in myotubes but not myogenic cells, unlike endogenous MyoD. Reporter expression in vivo is in muscle fibre nuclei and is reduced in MyoD null mice. The MD6.0-lacZ reporter is down-regulated both in adult muscle fibres by denervation or muscle disuse and in cultured myotubes by inhibition of activity. Activity induces and represses MyoD through the DRR and PRR, respectively. During the postnatal period, accumulation of beta-galactosidase correlates with maturation of innervation. Strikingly, endogenous MyoD expression is up-regulated in fibres by complete denervation, arguing for a separate activity-dependent suppression of MyoD requiring regulatory elements outside the DRR/PRR.


CONCLUSIONS
The data show that MyoD regulation is more complex than previously supposed. Two factors, MyoD protein itself and fibre activity are required for essentially all expression of the 6 kb proximal enhancer/promoter (DRR/PRR) of MyoD in adult fibres. We propose that modulation of MyoD positive feedback by electrical activity determines the set point of MyoD expression in innervated fibres through the DRR/PRR element.
Chargé
Sophie B
SB
Randall Division for Cell and Molecular Biophysics and the MRC Centre for Developmental Neurobiology, New Hunt's House, Guy's Campus, King's College London, London, UK. sophie@stemcellnetwork.ca
Brack
Andrew S
AS
Bayol
Stéphanie A
SA
Hughes
Simon M
SM
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D004558:Electric Stimulation; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D007763:Lac Operon; D051379:Mice; D008822:Mice, Transgenic; D009121:Muscle Denervation; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D017570:MyoD Protein / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*
D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein