Abstract
BackgroundInhibition of activin/myostatin pathway has emerged as a novel approach to increase muscle mass and bone strength. Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to progressive muscle degeneration and also high incidence of fractures. The aim of our study was to test whether inhibition of activin receptor IIB ligands with or without exercise could improve bone strength in the mdx mouse model for DMD.MethodsThirty-two mdx mice were divided to running and non-running groups and to receive either PBS control or soluble activin type IIB-receptor (ActRIIB-Fc) once weekly for 7 weeks.ResultsTreatment of mdx mice with ActRIIB-Fc resulted in significantly increased body and muscle weights in both sedentary and exercising mice. Femoral μCT analysis showed increased bone volume and trabecular number (BV/TV +80%, Tb.N +70%, P < 0.05) in both ActRIIB-Fc treated groups. Running also resulted in increased bone volume and trabecular number in PBS-treated mice. However, there was no significant difference in trabecular bone structure or volumetric bone mineral density between the ActRIIB-Fc and ActRIIB-Fc-R indicating that running did not further improve bone structure in ActRIIB-Fc-treated mice. ActRIIB-Fc increased bone mass also in vertebrae (BV/TV +20%, Tb.N +30%, P < 0.05) but the effects were more modest. The number of osteoclasts was decreased in histological analysis and the expression of several osteoblast marker genes was increased in ActRIIB-Fc treated mice suggesting decreased bone resorption and increased bone formation in these mice. Increased bone mass in femurs translated into enhanced bone strength in biomechanical testing as the maximum force and stiffness were significantly elevated in ActRIIB-Fc-treated mice.ConclusionsOur results indicate that treatment of mdx mice with the soluble ActRIIB-Fc results in a robust increase in bone mass, without any additive effect by voluntary running. Thus ActRIIB-Fc could be an attractive option in the treatment of musculoskeletal disorders.
Highlights
Inhibition of activin/myostatin pathway has emerged as a novel approach to increase muscle mass and bone strength
The role of activins in bone physiology remained unclear until recent studies indicated that inhibition of activin receptor ligands leads to increased bone mass [5, 6]
We aimed to answer the following questions: 1) does inhibition of activin receptor ligands with the use of a soluble activin type IIB-receptor (ActRIIB-Fc) affect bone volume and quality in a muscle dystrophy mouse model [24] parallel to changes in muscle mass and 2) is there an interaction between ActRIIB-Fc treatment and low-intensity aerobic exercise
Summary
Inhibition of activin/myostatin pathway has emerged as a novel approach to increase muscle mass and bone strength. The role of activins in bone physiology remained unclear until recent studies indicated that inhibition of activin receptor ligands leads to increased bone mass [5, 6]. In these experiments, soluble activin receptor-Fc fusion proteins were used as decoy receptors harvesting and inhibiting their ligands including activin A and myostatin. Soluble activin receptor-Fc fusion proteins were used as decoy receptors harvesting and inhibiting their ligands including activin A and myostatin These studies suggested that inhibition of activin pathway could be a promising therapeutic target for metabolic bone diseases [7]. Increasing body weight through muscle mass in combination with exercise has not been investigated before
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