Inhibitors of Tyrosine Phosphatases and Apoptosis Reprogram Lineage-Marked Differentiated Muscle to Myogenic Progenitor Cells

SummaryMuscle regeneration declines with aging and myopathies, and reprogramming of differentiated muscle cells to their progenitors can serve as a robust source of therapeutic cells. Here, we used the Cre-Lox method to specifically label postmitotic primary multinucleated myotubes and then utilized small molecule inhibitors of tyrosine phosphatases and apoptosis to dedifferentiate these myotubes into proliferating myogenic cells, without gene overexpression. The reprogrammed, fusion competent, muscle precursor cells contributed to muscle regeneration in vitro and in vivo and were unequivocally distinguished from reactivated reserve cells because of the lineage marking method. The small molecule inhibitors downregulated cell cycle inhibitors and chromatin remodeling factors known to promote and maintain the cell fate of myotubes, facilitating cell fate reversal. Our findings enhance understanding of cell-fate determination and create novel therapeutic approaches for improved muscle repair.

► Irreversible lineage marking of multinucleated myotubes by Cre-Lox method
► Small molecule inhibitors reprogram lineage-marked muscle to their progenitor cells
► Reprogrammed myogenic progenitor cells contribute to muscle regeneration in vivo