(190m) NANOG Restores the Myogenic Differentiation Potential of Senescent Myoblasts

Skeletal muscle loss due to aging, sarcopenia, is a major medical problem facing elderlies. 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 show that expression of embryonic transcription factor NANOG in late passage myoblasts restored their myogenic differentiation potential which was impaired due to cellular senescence. This reversal in the myogenic differentiation was proven both at the functional level, by formation of myotubes in 2D and 3D, and at the molecular level by restoring the expression level of myogenic regulatory factors (Myf5, Myod, Myogenin, and MRF4) and members of myocyte enhancer factor 2 family.

The anti-aging effects of NANOG were accompanied by pluripotency effects of NANOG on myoblasts, in which expression of NANOG in differentiation phase could inhibit myotube formation, therefore removal of this factor was required before the start of differentiation.

Interestingly, the rejuvenating effects of NANOG on senescent myoblasts were stable for 2 weeks after removal of this factor, suggesting that NANOG might have imparted epigenetic changes. This rescue of myogenic differentiation was accompanied by reversal of cellular morphology and amelioration of aging hallmarks (i.e. trimethylation of H3K9, reduction of reactive oxygen species, and decrease in the DNA damage marker gH2AX).

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.