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    ASBMR 2011 Annual Meeting

    Systemic Administration of Soluble Activin Receptors Produces Differential Anabolic Effects in Muscle and Bone in Mice

     Aging and Muscle/Bone Interactions
     Growth Factors, Cytokines and Immunomodulators

    Oral Presentations, Presentation Number: 1167
    Session: Concurrent Oral Session 28: Preserving Muscle and Bone during Aging
    Monday, September 19, 2011 11:00 AM - 11:15 AM, San Diego Convention Center, Room 20BCD

    * , UNITED STATES, Vandana Singhal, Johns Hopkins University, , Se-Jin Lee, Johns Hopkins University

    Myostatin and related activin ligands are powerful negative regulators of skeletal muscle growth.  Recent studies demonstrate that administration of soluble ActRII (ACVR2) fusion proteins, which sequester these muscle inhibitory factors, increases both skeletal muscle and bone mass in rodents and primates.  Whether the observed bone anabolism results from direct actions in osteoblasts or is secondary to the increased muscle mass is unclear.  To begin to address this question, 8 week-old female C57BL/6 mice were administered 10 mg/kg of ACVR2/Fc, ACVR2B/Fc or vehicle by IP injection, once a week, for 4 weeks.  Wet weights of pectoralis, triceps, quadriceps and gastrocnemius muscles were increased by ~15% over vehicle in mice receiving ACVR2/Fc and by 40% in mice treated with ACVR2B/Fc.  Micro CT analysis of the distal femur revealed a striking 3-fold increase in trabecular BV/TV in the ACVR2B/Fc group, but no significant change in cortical thickness at the midshaft.  By contrast, mice treated with ACVR2/Fc demonstrated a more modest increase in trabecular BV/TV (13.6% vs. 7.6% in controls), but also had significantly increased cortical thickness at the femoral midshaft (204.5μm vs. 162.1μm in controls).  Interestingly, ACVR2/Fc increased calvarial bone volume to a greater extent than ACVR2B/Fc.  The increase in calvarial bone (a non load-bearing bone) and rapid accrual of trabecular bone in mice administered ACVR2B/Fc suggested direct actions of activin receptor signaling in bone.  Consistent with this notion, real-time PCR performed on mRNA from primary mouse osteoblasts revealed expression of activin receptors and ligands at levels comparable to those seen in skeletal muscle, with the exception of myostatin, which was not expressed by osteoblasts.  Additionally, phosphorylation of Smad2, an immediate substrate of activin receptor activation, was decreased in a time- and dose-dependent manner following exposure of osteoblasts to ACVR2B/Fc.  These changes in Smad phosphorylation were accompanied by a modest decrease in osteoblast proliferation as indexed by BrdU incorporation.  To further explore the effects of blocking activin receptor signaling on osteoblast performance, osteoblasts were differentiated in the presence of ascorbic acid and β-glycerophosphate, with or without increasing concentrations of ACVR2B/Fc.  Alkaline phosphatase and alizarin red staining were increased in osteoblasts treated with ACVR2B/Fc versus control.  Taken together, our results suggest that activin receptor signaling functions directly in osteoblasts to regulate bone mass.  Further, ACVR2/Fc and ACVR2B/Fc exerted differential anabolic activity in bone and muscle, an attractive property for a potential therapy for osteopenia and/or sarcopenia. 

    Disclosures: None

    * Presenting Authors(s): , UNITED STATES