Administration of a soluble activin type IIB receptor promotes skeletal muscle growth independent of fiber type

Abstract

This is the first report that inhibition of negative regulators of skeletal muscle by a soluble form of activin type IIB receptor (ACE-031) increases muscle mass independent of fiber-type expression. This finding is distinct from the effects of selective pharmacological inhibition of myostatin (GDF-8), which predominantly targets type II fibers. In our study 8-wk-old C57BL/6 mice were treated with ACE-031 or vehicle control for 28 days. By the end of treatment, mean body weight of the ACE-031 group was 16% greater than that of the control group, and wet weights of soleus, plantaris, gastrocnemius, and extensor digitorum longus muscles increased by 33, 44, 46 and 26%, respectively (P<0.05). Soleus fiber-type distribution was unchanged with ACE-031 administration, and mean fiber cross-sectional area increased by 22 and 28% (P<0.05) in type I and II fibers, respectively. In the plantaris, a predominantly type II fiber muscle, mean fiber cross-sectional area increased by 57% with ACE-031 treatment. Analysis of myosin heavy chain (MHC) isoform transcripts by real-time PCR indicated no change in transcript levels in the soleus, but a decline in MHC I and IIa in the plantaris. In contrast, electrophoretic separation of total soleus and plantaris protein indicated that there was no change in the proportion of MHC isoforms in either muscle. Thus these data provide optimism that ACE-031 may be a viable therapeutic in the treatment of musculoskeletal diseases. Future studies should be undertaken to confirm that the observed effects are not age dependent or due to the relatively short study duration.

Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway

“…Interfering with MSTN signalling increases tolerance to glucose To ascertain whether or not interfering with MSTN signalling postnatally has a similar effect to that observed in Mstn −/− mice, WT mice fed on HFD were treated with sActIIBR, which has been previously shown to act as a potent antagonist to MSTN activity [34,35]. Treatment with sActIIBR reduced the insulin resistance seen in mice fed on a HFD.…”

Targeting the Activin Type IIB Receptor to Improve Muscle Mass and Function in the mdx Mouse Model of Duchenne Muscular Dystrophy

“…54 Recently, a humanized version of sActRIIB (ACE-031), composed of the extracellular portion of the human ActRIIB fused to a human Fc, has been reported to produce similar effects (ie, improved muscle mass and strength) in wild-type mice. 55 In addition to the effects noted of sActRIIB on muscle mass and function, sActRIIB therapy resulted in lower circulating CK levels, compared with saline-treated control mice. The reduced CK levels occurred despite no clear improvements in skeletal muscle histopathology, nor any changes in sarcolemmal integrity as accessed via Procion Orange uptake.…”

Inhibiting myostatin reverses muscle fibrosis through apoptosis

“…Two-year-old mdx mice were systemically administered PBS as control or 10 mg/kg ActRIIB.mFc for 6 weeks, a dose previously determined to induce muscle hypertrophy in wild-type mice (Akpan et al, 2009;Cadena et al, 2010;Lachey et al, 2007;Morrison et al, 2009). Apoptotic cells in the interstitial space between muscle fibers were identified by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and by immunohistochemistry assay of cleaved caspase-3 (Fig.…”