Enhanced HGF with increased receptor affinity and nitration-dysfunction resistance through interaction with lipoic...

Myogenic stem cell activator HGF (hepatocyte growth factor) undergoes nitration of tyrosine residues (Y198, Y250) predominantly on fast-twitch fibers to lose its binding affinity to the signaling receptor c-met, in response to peroxynitrite (ONOO^-) generation during aging. Here we show that HGF adopts an enhanced form with dynamically increased receptor-binding affinity and nitration-dysfunction resistance through interaction with lipoic acid trisulfide (LASSS) under physiological conditions. When evaluated after exposure to LASSS at a 1:8000 molar ratio to HGF and subsequent ultra-filtration to wash-out un-reacted free LASSS, c-met binding affinity increased more than two-fold over the original non-nitrated HGF. The same LASSS treatment also conferred nitration resistance with a greater effect for Y198 than Y250, indicating a novel mechanism independent of an anti-oxidative function of LASSS. Neither glutathione trisulfide (GSSSG, a potent anti-oxidant) nor lipoic acid enhanced c-met binding or nitration resistance, and thus served as controls. Importantly, pre-administration of LASSS to mice prevented the disuse-induced HGF nitration observed in a tail-suspension model for muscle atrophy, while GSSSG did not. The findings encourage the idea that LASSS may react with HGF to enhance its receptor-binding affinity and nitration resistance, which are known to strongly drive myogenic stem cell dynamics and homeostasis. Application of this model could potentially lead to pioneering strategies to counteract or treat age-related muscle atrophy and impaired regeneration with fibrosis and fat infiltration (including sarcopenia and frailty).