๐ค Authors: Frederik Duch Bromer, Andreas Lodberg, Marco Eijken, Christian Brix Folsted Andersen, Mathias Flensted Poulsen, Jesper Skovhus Thomsen, Annemarie Brรผel
The Effect of Anti-Activin Receptor Type IIA and Type IIB Antibody on Muscle, Bone and Blood in Healthy and Osteosarcopenic Mice.
Anti-Activin Receptor Type IIA and Type IIB antibody (ฮฑActRIIA/IIB ab) is a recently developed drug class that targets the activin receptor signalling pathway. Inhibition of receptor ligands (activins, myostatin, growth differentiation factor 11, etc.) can lead to skeletal muscle hypertrophy, bone formation, and increased haematopoiesis.
Despite the ฮฑActRIIA/IIB ab, bimagrumab, having progressed to clinical trials, two crucial questions about ฮฑActRIIA/IIB ab therapy remain: Does ฮฑActRIIA/IIB ab influence bone metabolism and bone strength similarly to its generic classmates (activin receptor-based ligand traps)? Does ฮฑActRIIA/IIB ab affect red blood cell parameters, thereby increasing the risk of thromboembolism, similar to its generic classmates?
Therefore, the aim of the present study was to investigate the therapeutic potential of ฮฑActRIIA/IIB ab in a mouse model of concurrent sarcopenia and osteopenia and to investigate the effect on bone and haematopoiesis in more detail. In C57BL/6JRj mice, combined sarcopenia and osteopenia were induced locally by injecting botulinum toxin A into the right hindlimb, resulting in acute muscle paresis.
Immediately after immobilization, mice received twice-weekly intraperitoneal injections with ฮฑActRIIA/IIB ab (10โmg/kg) for 21โdays, after which they were sacrificed. Muscle mass, skeletal muscle fibre size and Smad2 expression were analysed in the rectus femoris and gastrocnemius muscles.
Bone mass and bone microstructure were analysed in the trabecular bone at the distal femoral metaphysis, while the cortical bone was analysed at the femoral mid-diaphysis. In a substudy, the effect on haematopoiesis was explored 2 and 7โdays after a single ฮฑActRIIA/IIB ab (30โmg/kg) injection in C57BL/6JRj mice. ฮฑActRIIA/IIB ab caused a large increase in muscle mass in both healthy (+21%) and immobilized (sarcopenic and osteopenic) (+12%) mice.
Furthermore, ฮฑActRIIA/IIB ab increased trabecular bone (bone volume fraction) for both healthy (+65%) and immobilized (+44%) mice. For cortical bone, ฮฑActRIIA/IIB ab caused a small, but significant, increase in bone area (+6%) for immobilized mice, but not for healthy mice.
Treatment with ฮฑActRIIA/IIB ab did not change red blood cell count, haemoglobin concentration or mean cell volume after either 2 or 7โdays. Treatment with ฮฑActRIIA/IIB ab caused a significant increase in both skeletal muscle mass and bone parameters in both healthy and immobilized mice, suggesting a potential in the treatment of concurrent osteopenia and sarcopenia.
Interestingly, the bone anabolic effect of the treatment was much more pronounced on trabecular bone than on cortical bone. There was no pronounced effect of short-term treatment on haematopoiesis.
