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

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.

Interferon beta augments tuberous sclerosis complex 2 (TSC2)-dependent inhibition of TSC2-null ELT3 and human lymphangioleiomyomatosis-derived cell proliferation.

Lymphangioleiomyomatosis (LAM), a rare pulmonary disorder, manifests as an abnormal neoplastic growth of smooth muscle-like cells within the lungs. Mutational inactivation of tumor suppressor tuberous sclerosis complex 2 (TSC2) in LAM constitutively activates the mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) signaling pathway and promotes neoplastic growth of LAM cells. In many cell types, type I interferon beta (IFNbeta) inhibits proliferation and induces apoptosis through signal transducers and activators of transcription (STAT)-dependent and STAT-independent signaling pathways, one of which is the mTOR/S6K1 signaling pathway. Our study shows that IFNbeta is expressed in LAM tissues and LAM-derived cell cultures; however, IFNbeta attenuates LAM-derived cell proliferation only at high concentrations, 100 and 1000 U/ml (IC(50) value for IFNbeta is 20 U/ml compared with 1 U/ml for normal human mesenchymal cells, human bronchus fibroblasts and human airway smooth muscle cells). Likewise, IFNbeta only attenuates proliferation of smooth muscle TSC2-null ELT3 cells. Analysis of IFNbeta signaling in LAM cells showed expression of IFNbeta receptor alpha (IFNbetaRalpha) and IFNbetaRbeta, activation and nuclear translocation of STAT1, and phosphorylation of STAT3 and p38 mitogen-activated protein kinase (MAPK), but IFNbeta had little effect on S6K1 activity. However, the re-expression of TSC2 or inhibition of mTOR/S6K1 with rapamycin (sirolimus) augmented antiproliferative effects of IFNbeta in LAM and TSC2-null ELT3 cells. Our study demonstrates that IFNbeta-dependent activation of STATs and p38 MAPK is not sufficient to fully inhibit proliferation of cells with TSC2 dysfunction and that TSC2-dependent inhibition of mTOR/S6K1 cooperates with IFNbeta in inhibiting human LAM and TSC2-null ELT3 cell proliferation.