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.
Cadena
Samuel M
SM
Acceleron Pharma Inc., 128 Sidney St., Cambridge, MA 02139, USA.
Tomkinson
Kathleen N
KN
Monnell
Travis E
TE
Spaits
Matthew S
MS
Kumar
Ravindra
R
Underwood
Kathryn W
KW
Pearsall
R Scott
RS
Lachey
Jennifer L
JL
D030301:Activin Receptors, Type II / Q000008:administration & dosage* / Q000235:genetics; D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D006984:Hypertrophy; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024510:Muscle Development / Q000187:drug effects*; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D055435:Myostatin / Q000037:antagonists & inhibitors; D009929:Organ Size; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D013997:Time Factors; D015430:Weight Gain
D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; C525912:Mstn protein, mouse; D055435:Myostatin; D020033:Protein Isoforms; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B; D018995:Myosin Heavy Chains
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