Glucocorticoids are the standard of care for boys with Duchenne muscular dystrophy (DMD), with treatment starting shortly after diagnosis (generally at 4-5 years old), resulting in better long-term outcomes. However, chronic glucocorticoid use has a catabolic effect on muscle and bone, highlighted by muscle loss and an increased risk of lumbar fractures. TGF-β family members, including activin A, activin B and myostatin, are potent negative regulators of musculoskeletal growth. RKER-065 is the research form of KER-065, an investigational, modified type II activin receptor ligand trap that inhibits these ligands. This study aims to determine if RKER-065 prevents the negative musculoskeletal effects of glucocorticoids in young mice.
Two-week-old male C57BL/6 mice received vehicle (Veh, PBS, i.p., QD) or prednisolone (Pred; 4mg/m2, i.p., QD), and either tris-buffered saline (TBS, i.p., BW) or RKER-065 (10mg/kg, i.p, BW), for 8 weeks. All animals were assessed for body weight, lean mass, grip strength, lumbar spine bone mineral density (BMD), and bone micro-architecture.
Chronic treatment with prednisolone (Pred-TBS) resulted in 61% less lean mass than vehicle-treated (Veh-TBS) mice. Co-treatment with RKER-065 and prednisolone increased lean mass to levels similar to Veh-TBS mice, suggesting protection against prednisolone-induced muscle atrophy. There were also corresponding changes observed in muscle function. The grip strength of the Pred-TBS group was lower than Veh-TBS (p=0.069), while the Pred-RKER-065 group’s grip strength was increased (p=0.0003) compared to Pred-TBS treatment. Prednisolone treatment was associated with decreased lumbar spine BMD. Compared to Pred-TBS treatment, co-treatment with RKER-065 was associated with improved BMD and a significant increase in the trabecular bone volume fraction.
Our data demonstrate that RKER-065 can attenuate the negative musculoskeletal effects of chronic glucocorticoid use in young mice. Therefore, KER-065 has the potential to improve muscle mass, muscle function, and bone health in DMD patients receiving chronic glucocorticoid treatment.