ACE-083 increases muscle hypertrophy and strength in C57BL/6 mice

ACE-083 is a locally-acting investigational protein therapeutic that acts as a ligand trap for the Transforming Growth Factor-Beta (TGF-β) superfamily which negatively regulate muscle mass. ACE-083 has been engineered to increase muscle mass and strength selectively in the muscle in which it has been administered. We have previously demonstrated that in mice ACE-083 induced muscle hypertrophy locally in a dose-dependent fashion with no effects on other muscle groups. To determine if the observed hypertrophy provided a functional benefit to the muscle we performed a study in which the tibialis anterior (TA) of mice was injected with ACE-083 or with vehicle control twice per week for 4 weeks. At study termination, the TA muscle was prepared for in situ physiologic studies. After testing, the muscle was then dissected free for histological analyses. Histological analysis demonstrated that ACE-083 treatment induced significant hypertrophy of the injected TA muscle fibers with no observable effect on the contralateral muscle or in comparison to vehicle treated controls. ACE-083 treatment increased the absolute twitch force of the TA muscle by 52% and absolute tetanic force by 39% relative to vehicle control. In addition, ACE-083 also increased the absolute peak power of the TA by 41% compared to vehicle control. Other factors that determine power output, such as maximal shortening velocity or the shape of the force-velocity curves, were not affected by ACE-083 treatment. This indicates that ACE-083 treatment did not alter the intrinsic properties of the muscle and the increase in force was due to hypertrophy. These data demonstrate that ACE-083 induced muscle hypertrophy provides a functional benefit through increases in force and power. The data suggest that ACE-083 may be effective as a therapeutic agent for focal myopathies, such as inclusion body myositis or facioscapulohumeral muscular dystrophies.