Co-Administration of Myostatin-Targeting siRNA and ActRIIB-Fc Fusion Protein Increases Masseter Muscle Mass and Fiber Size

Abstract

Summary Myostatin, a member of the TGF-␤ superfamily, is a negative regulator of skeletal muscle cell growth and differentiation, and binds with high affinity to the activin type IIB receptor (ActRIIB). The soluble ligand-binding domain of ActRIIB fused to the Fc domain of IgG (ActRIIB-Fc) potently binds and inhibits TGF-␤ family members in muscle, leading to rapid and marked muscle growth. The present study was designed to assess the effectiveness of the co-delivery of myostatin-targeting siRNA (Mstn-siRNA) and ActRIIBFc into skeletal muscle as a potential treatment of atrophic myopathies. Eleven-week-old, male C57BL/6 mice were injected with atelocollagen (ATCOL)-mediated Mstn-siRNA with/ without ActRIIB-Fc locally into the masseter muscle twice a week. Inhibition of myostatin function by the combination of Mstn-siRNA and ActRIIB-Fc increased muscle weight and myofibril size in murine masseter muscle. Real-time RT-PCR analysis revealed significant downregulation of myostatin mRNA expression in both the Mstn-siRNA-treated and the combination treatment group. Furthermore, myogenin mRNA expression was upregulated in the combination treatment group, while MuRF-1 and Atrogin-1 mRNA expression was downregulated compared to administration of each compound alone. These findings suggest that double inhibition of myostatin is a potentially useful treatment strategy to increase muscle mass and fiber size and could be a useful treatment of patients with various muscle atrophies, including muscular dystrophy.

ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension

“…GDF8 is highly homologous to GDF11 (~90%) (33) and overlaps in function with GDF11 and activin A in regulating muscle mass and myocyte hypertrophy based on genetic loss-of-function and pharmacologic experiments (34,35). Targeting GDF8, GDF11, and activin ligands as a group versus individually has proven to be more effective for increasing muscle mass (36)(37)(38). By analogy, it is likely that this set of ligands of ACTRIIA may have overlapping roles in pulmonary vascular disease.…”

A Clinical Pilot Study Showing the Safety and Efficacy of Intramuscular Injection of Atelocollagen for Prevention of Paraspinal Muscle Atrophy after Spine Surgery

“…Several studies have demonstrated surgical role of atelocollagen and promising clinical results have been reported [8,16,21,23,25]. In a recent study using atelocollagen in orthopaedic surgery, Suh et al [26] suggested repair after using patch-type atelocollagen between the torn rotator cuff and bone using rabbits.…”

“…Highly purified atelocollagen is low in immunogenicity because it is free from telopeptides and has many advantages for biocompatibility and optimizing collagen-cell interaction for efficacy and lower side effects [7]. Studies using human subjects and experimental animals have shown that atelocollagen provides good therapeutic results by promoting cell proliferation and early epithelialization while causing little rejection and few complications [8].…”

Application of purified porcine collagen in patients with chronic refractory musculoskeletal pain

“…Therefore, it is estimated that PAC might have acted as a scaffold to facilitate the tissue regeneration reaction around damaged tissue in the present study. In this respect, it is possible that using progenitor cells or proliferation-related factors may have a synergistic effect [19,24,25]. Finally, the effect might have been caused by the reduction of inflammation.…”