Increased Muscle Force Production and Bone Mineral Density in ActRIIB-Fc-Treated Mature Rodents

Abstract

Myostatin is a highly conserved member of the transforming growth factor-β ligand family known to regulate muscle growth via activation of activin receptors. A fusion protein consisting of the extracellular ligand-binding domain of activin type IIB receptor with the Fc portion of human immunoglobulin G (ActRIIB-Fc) was used to inhibit signaling through this pathway. Here, we study the effects of this fusion protein in adult, 18-month-old, and orchidectomized mice. Significant muscle growth and enhanced muscle function were observed in adult mice treated for 3 days with ActRIIB-Fc. The ActRIIB-Fc-treated mice had enhanced fast fatigable muscle function, with only minor enhancement of fatigue-resistant fiber function. The ActRIIB-Fc-treated 18-month-old mice and orchidectomized mice showed significantly improved muscle function. Treatment with ActRIIB-Fc also increased bone mineral density and serum levels of a marker of bone formation. These observations highlight the potential of targeting ActRIIB receptor to treat age-related and hypogonadism-associated musculoskeletal degeneration.

Mitochondrial impairment induced by postnatal ActRIIB blockade does not alter function and energy status in exercising mouse glycolytic muscle in vivo

“…It is then conceivable that the long-term ActRIIB blockade produces similar alterations, hence ultimately lowering the ability to generate tetanic tension. Last, we found that ActRIIB signaling inhibition reduced fatigue resistance during the in vivo fatiguing exercise, which corroborates other studies showing that sActRIIB-Fc delivery increases fatigability in hindlimb muscle electrically stimulated in situ (15) and decreases the time to exhaustion during incremental speed running tests (52).…”

“…Third, we observed that sActRIIB-Fc treatment did not improve maximal tetanic force in vivo. Although counterintuitive, this finding has already been reported in isolated muscles from myostatin-deficient mice (2) or from wild-type mice treated with sActRIIB-Fc (1,15) or myostatin neutralizing antibodies (36). While the underlying cause for this phenomenon has not been documented, one must be aware that myostatin deficiency reduces the relative collagen content, which alters muscle mechanistically by increasing the stiffness of muscle aponevrosis and tendon (43,59).…”

“…This issue is, however, an important prerequisite for a better understanding of the effects of ActRIIB blockade in diseased muscle. It has been shown that postnatal disruption of ActRIIB signaling in normal mice improves functional parameters such as grip strength (1,33) and absolute force in isolated muscle (1,15) but on the other hand decreases resistance to fatigue (15,52). These results are in all respects comparable to those obtained in myostatin-deficient mice in which improved force has been documented (2,19,43,45) and the increased fatigability has been assigned to a mitochondrial impairment evidenced on the basis of in vitro assays (45,48) and in vivo 31 P-MRS measurements (6,19).…”

Inhibiting myostatin signaling prevents femoral trabecular bone loss and microarchitecture deterioration in diet-induced obese rats

“…[25][26][27] On the other hand, MSTN blocking or deficiency has been shown to enhance bone formation. 28,29 However, we still have much to learn regarding whether inhibiting MSTN can reduce obesity-induced bone loss, and if so, what possible mechanisms might be responsible. Our findings demonstrated that blocking MSTN by MsAb preserves bone microstructure and that this effect may involve the accompanying changes occurring in the levels of circulating adiponectin and pro-inflammatory cytokines.…”

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

“…Several strategies have been developed in the last decade for the treatment of muscular dystrophy and muscle wasting based on myostatin inhibition, myostatin-specific antibodies (1,2), a decoy myostatin receptor (3,4), and myostatin propeptide (5,6). Furthermore, two studies showed that myostatin knockout in mice (e.g., the mdx mouse model of Duchenne muscular dystrophy) resulted in a significant increase in skeletal muscle mass and functional improvement in dystrophic muscles (7,8).…”