NANOG Restores the Myogenic Differentiation Potential of Senescent Myoblasts

Skeletal muscle loss due to aging, sarcopenia, is a major challenge facing the elderly. Adult skeletal muscle regeneration relies on the activity of resident satellite cells in skeletal muscle niche. However, systemic and intrinsic factors decrease the myogenic differentiation potential of senescent satellite cells. Here we employed a doxycycline (Dox) regulatable system to show that expression of the embryonic transcription factor NANOG restored the impaired myogenic differentiation potential of senescent myoblasts. This reversal in the myogenic differentiation was shown at the functional level by formation of myotubes in 2D and 3D, and at the molecular level by restoring the expression level of key myogenic regulatory factors such as Myf5, Myod, Myogenin, and MRF4 and members of myocyte enhancer factor 2 family. Interestingly, the rejuvenating effects of NANOG on senescent myoblasts were sustained after withdrawal of Dox. The myoblasts maintained their rejuvenated capacity up to a month after NANOG withdrawal, suggesting that NANOG might have imparted epigenetic changes. In conclusion, these results shed light on the potential of NANOG to restore the myogenic differentiation potential of senescent myoblasts and to reverse the loss of muscle regeneration due to aging.