Muscle differentiation going down the tube

Abstract

Mammalian myotube terminal differentiation was previously believed to result in an irreversible differentiation process – evidenced by the downregulation of cyclins and cyclin-dependent kinases (CDKs) and through the expression of CDK inhibitors, retinoblastoma genes, muscle differentiation factors such as myogenin and contractile proteins such as troponin. However, Odelberg et al.1xDedifferentiation of mammalian myotubes induced by msx1. Odelberg, S.J et al. Cell. 2000; 103: 1099–1109Abstract | Full Text | Full Text PDF | PubMed | Scopus (325)See all References1 now report that a nuclear protein, msx1, can reverse myotube differentiation, and the resulting cells can be induced to differentiate into other cell types.The authors transduced the mouse msx1 gene into C2C12 myoblasts and found that the expression of msx1 prevented myotube formation. When msx1 was expressed in the presence of growth medium, the levels of MRF4, p21 and myogenin were reduced. This was followed by the reduction of MyoD expression. By plating myotubes at low density together with growth medium stimulation, they also showed that msx1 expression led to the cleavage of large myotubes into smaller tubes or proliferating mononucleated cells. The de-differentiated clones were then tested in different culture conditions for pluripotency. In chondrogenic differentiation medium, the de-differentiated myotube clones expressed collagen type II and could be further induced to express collagen type X. In adipogenic differentiation medium, adipocyte morphology was induced and numerous vacuoles stained positive in the presence of lipophilic dyes. In osteogenic medium, in addition to foci staining with alkaline phosphatase, osteogenic markers such as osteocalcin and osteopontin were detected. Furthermore, when msx1expression was deliberately switched off, chondrogenic, adipogenic, myogenic or osteogenic markers could still be detected under various differentiation conditions, suggesting that trans-determination had occurred.These data show that mammalian myotubes can be de-differentiated, and the de-differentiated cells have properties characteristic of stem cells. As the authors point out, the molecular mechanisms underlying msx1 activities are still unknown. It remains to be discovered whether msx1 can interfere with factors that affect maintenance of differentiation and in so doing regulate the inheritance of different differentiation states.