Increasing evidence implicates skeletal muscle as an active contributor to amyotrophic lateral sclerosis (ALS) pathology. Activin A and myostatin are potent negative regulators of skeletal muscle growth and regeneration. The benefits observed in ALS animal models, achieved by inhibiting activin/myostatin signaling, also highlight the critical role of muscle-derived cues. RKER-065 is research version of a modified type II activin receptor ligand trap designed to inhibit myostatin and activins. This proof-of-concept study examined the treatment effects of RKER-065 in an ALS mouse model.
Six-week-old male SOD1-G93A (SOD1) mice were intraperitoneally injected with vehicle (Veh mice) or RKER-065 (10mg/kg, BIW) for 8 weeks. Vehicle-treated B6SJL/J mice served as controls (WT).
Compared with WT controls, Veh mice exhibited reduced body and skeletal muscle weight, reduced grip strength (GSM), significantly elevated inflammation markers in muscle and declined compound muscle action potential (CMAP) amplitude and action potential amplitude following repetitive nerve stimulation (RNS). In contrast, RKER-065-treated SOD1 mice had significantly higher body and muscle weight than Veh mice. qPCR analysis revealed a reduced inflammatory profile of macrophages, with a significant decrease in CD86 and an increase in CD206 and IL-10 expression in RKER-065-treated relative to Veh mice. This was associated with improved muscle function; RKER-065-treated SOD1 mice exhibited a 53% increase in GSM versus Veh mice. CMAP amplitude did not differ significantly between RKER-065 group and Veh group. However, the action potential amplitude of the tibialis anterior muscle following RNS was significantly greater in RKER-065-treated SOD1 mice than in Veh mice at three of the four tested frequencies, indicating improved neuromuscular transmission and enhanced fatigue resistance.
Our findings suggest that dual inhibition of myostatin and activins with RKER-065 has the potential to preserve muscle mass, muscle function, and neuromuscular junction integrity, and reduce inflammation in ALS.