GASP-2 overexpressing mice exhibit a hypermuscular phenotype with contrasting molecular effects compared to GASP-1 transgenics

Muscle atrophy is associated with many diseases including genetic disorders, sarcopenia, or cachexia syndromes. Myostatin (Mstn), a transforming growth factor-beta (TGF-beta) member, plays a key role in skeletal muscle homeostasis as a powerful negative regulator. Over the last decade, about 15 clinical trials aimed at inhibiting the Mstn pathway, failed to produce conclusive results. In this context, we investigated whether growth and differentiation factor-associated serum protein-1 (GASP-1) or GASP-2, two natural inhibitors of Mstn, might represent a potential therapeutic. As we previously reported, mice overexpressing Gasp-1 (Tg(Gasp-1)) present an increase of muscle mass but develop metabolic disorders with aging. Here, we showed that overexpression of Gasp-2 increases the muscular mass without metabolic defects. We also found that Tg(Gasp-2) mice displayed, like Mstn(-/-) mice, a switch from slow- to fast-twitch myofibers whereas Tg(Gasp-1) mice exhibit a reverse switch. Our studies supported the fact that GASP-2 has less affinity than GASP-1 for Mstn, leading to a constitutive Mstn upregulation only in Tg(Gasp-1) mice, responsible for the observed phenotypic differences. Altogether, our findings highlighted a gene expression regulatory network of TGF-beta members and their inhibitors in muscle