A role for Maged1 in skeletal myogenic differentiation and muscle regeneration

Abstract

Maged1 is a member of the large family of MAGE proteins that were initially identified as tumour antigens. The molecular and physiological functions of the MAGE proteins remain largely to be clarified, but they act probably as adaptor or scaffolding proteins able to modulate the function of transcription factors and membrane receptors. Maged1 was previously shown to be essential for the developmental apoptosis of neurons initiated by the p75NTR neurotrophin receptors. Very recently, Maged1 was shown to regulate the circadian cycle by modulating the activity of the orphan nuclear receptor RORα. The work presented here unveils the importance of Maged1 in myogenic differentiation and muscle regeneration. In normal adult skeletal muscle, cell turnover is very slow. However, after an acute lesion or in chronic pathological conditions, such as primary myopathies, muscle stem cells, called satellite cells, are induced to proliferate, exit definitively from the cell cycle and fuse to form new muscle fibres. We show that Maged1 is expressed at very low levels in normal adult muscle but is strongly induced after injury, during the early phases of myoblast differentiation. By analyzing primary myoblasts derived from Maged1 knockout mice, we show that Maged1 deficiency results in reduced levels of p21CIP1/WAF1, Adam12 and Itgb1, leading to defective cell cycle exit and impaired myotube maturation. Our data suggest that Maged1 regulates the transcriptional activity of the key muscle transcription factors MyoD and Mef2C, explaining the myogenic differentiation failure. In vivo, we show that Maged1 deficiency results in delayed regeneration of muscles injured experimentally, confirming the physiological role of Maged1 in this process.

Date of Award	18 Aug 2010
Original language	English
Awarding Institution	University of Namur
Supervisor	Olivier De Backer (Supervisor), Yves Poumay (President), Nathalie Caron (Jury), Jean-Marc Raymackers (Jury) & Françoise Muscatelli (Jury)