Active immunization against myostatin and activin A improves skeletal muscle performance in growth hormone-deficient mice.

Abstract

Sarcopenia is a significant age-related hurdle in older adults due to immobilization, prolonged bed rest, loss of resilience, and diminished quality of life. Despite its high prevalence, there are no FDA-approved drugs for sarcopenia to date, underscoring the critical need to explore novel therapeutics. Here, we explore an active immunization strategy to suppress the activity of negative regulators of muscle growth, specifically myostatin and activin A. Importantly, our primary objective was to determine whether long-term MSTN/Act A inhibition can enhance muscle performance independently of hypertrophy, under conditions of impaired GH/IGF-1 signaling. Using a long-lived growth hormone (GH)-deficient murine model, we investigated whether myostatin and activin A immunization improves muscle strength, independently of changes in muscle mass. We showed that, while in the presence of GH, this immunization increases lean mass and grip strength improvement. Notably, in the GH-deficient mice, grip strength is independent of muscle mass gain. Myostatin inhibition modulated transcriptomic shift in the gastrocnemius muscle, allowing for remodeling of the skeletal muscle and an increase in energy expenditure. Consistent with these findings, aged mice subjected to the same immunization schedule exhibited improved grip strength, along with alterations in lipid metabolism within the gastrocnemius muscle. Altogether, these results suggest that this inhibition strategy alters the contractility of the skeletal muscle, allowing for enhanced performance and offering a promising therapeutic strategy for muscle wasting.