Advanced glycation end product-its receptor axis participates in myoblast senescence in vitro and delayed muscle regeneration of senescence/aging skeletal muscles in vivo.

Abstract

The global population is rapidly aging, leading to a significant increase in age-related diseases in the coming years. Muscle dysfunction is a prevalent chronic condition among older adults, posing significant public health challenges. One of the key age-related changes in muscle tissue is the accumulation of advanced glycation end products (AGEs). Previous studies have reported that AGEs are highly associated with muscle dysfunction, particularly in diabetes. However, the relationship between AGEs and muscle aging still remains to be clarified. This study aimed to investigate the effects of AGEs on muscle repair function and regeneration through cellular and senescence/aging animal models. In cell model, the non-cytotoxic concentrations of AGEs induced cell senescence and inhibited myogenic differentiation in C2C12 myoblasts, as evidenced by senescence-associated β-galactosidase staining and hematoxylin and eosin (H&E) staining. These effects by AGEs could be restored by the treatment of neutralized antibody for receptor for AGEs (RAGE). In a d-galactose-accelerated senescence/aging mouse model, the immunohistochemistry staining showed a substantial AGEs accumulation and RAGE expression in the muscles, which could be reversed by AGEs inhibitor aminoguanidine treatment. In a model of muscle regeneration by glycerol injection in the tibialis anterior muscle, the muscle regeneration/repair capacity was significantly impaired and the Pax7 and MyoD expression was reduced in aging mice, which could also be reversed by aminoguanidine treatment. These findings suggest that AGEs-RAGE axis promote myoblast senescence, inhibit their differentiation, and it may impair muscle repair capacity in aging animals. Further research is needed to elucidate the underlying mechanisms.