The ActRIIB receptor. By Emw - Own work. Licensed under the Creative Commons Attribution-Share Alike 3.0 (CC BY-SA 3.0)

The ActRIIB receptor. By Emw - Own work. Licensed under the Creative Commons Attribution-Share Alike 3.0 (CC BY-SA 3.0)

ACE-031 is a soluble form of the IIB subtype of the activin receptor type, also known as ActRIIB1. Therefore, it is thought to have a positive effect on muscle growth via the inhibition of myostatin and other proteins involved in the regulation of muscle mass1,2. Some researchers conclude that ActRIIB is the receptor for myostatin, and that their complex mediates a pathway leading to the negative regulation of muscle mass3. This may be substantiated by observations of significantly increased skeletal muscle in animals expressing mutant ActRIIB (i.e. ActRIIB to which myostatin could not bind)4. Soluble ActRIIB is synthesized through the conjugation of an active domain of this receptor (e.g. the extracellular component) with another protein such as a fragment of a murine or human immunoglobulin3. This peptide has demonstrated the ability to significantly enhance muscle mass and performance in adult, young and castrated male mice2. Another study demonstrated the ability of a two-week regimen of treatment with this soluble receptor to increase skeletal muscle in mice by as much as 60%4.

ACE-031 and Androgen Deprivation

This peptide may counteract the effects of androgen deficiency5. This condition involves reductions in the production or biological activity of male hormones such as testosterone, and may occur as a result of aging or hypogonadism. It is associated with reductions in bone density, muscle mass and adipose tissue regulation5. An animal study treated both castrated and control mice with either soluble ActRIIB or an identical placebo. The soluble ActRIIB treatment resulted in significant increases in non-adipose tissue mass in both the control and castrated animals compared to changes associated with the placebo treatment5. Soluble ActRIIB was also associated with significant changes in adiposity compared to placebo, but only in the castrated animals5. The researchers also reported that treatment with the peptide also prevented steatohepatosis (the development of fatty liver disease), changed insulin levels and promoted bone density retention in castrated animals5. Another study of the effects of soluble ActRIIB on 18-month-old, castrated and adult mice respectively also reported positive effects on bone density and a marker of bone growth2. Therefore, ACE-031 may help to prevent androgen deficiency, which is seen as a disease in mammals that requires treatment by some researchers5. 

ACE-031 and its Role in Muscle Growth

Soluble ActRIIB may significantly improve muscle mass and strength in animal studies, as outlined above. However, when researchers analyzed this effect in more detail, they found that the peptide had the most beneficial effects on muscle fiber types with reduced fatigue-resistance, compared to other more resistant types2. This may be related to the actions of myostatin, which have been shown to concentrate on one specific fiber type (i.e. type II)6. Therefore, the positive effects of ACE-031 on muscle mass may be restricted to the acute, or relatively short-term. However, other research has shown that ACE-031 increases growth in multiple muscle fiber types indiscriminately6. In addition, ACE-031 does not bind exclusively to myostatin, but to other similar proteins such as GDF11 and (as the receptor name suggests) activin3. Therefore, its effects on muscle mass may extend beyond the simple antagonism of myostatin. 

References:

1. Attie KM, Borgstein NG, Yang Y, et al. A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers. Muscle & nerve. 2013;47(3):416-423.

2. Chiu CS, Peekhaus N, Weber H, et al. Increased muscle force production and bone mineral density in ActRIIB-Fc-treated mature rodents. The journals of gerontology. Series A, Biological sciences and medical sciences. 2013;68(10):1181-1192.

3. Rahimov F, King OD, Warsing LC, et al. Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor. Physiological genomics. 2011;43(8):398-407.

4. Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(16):9306-9311.

5. Koncarevic A, Cornwall-Brady M, Pullen A, et al. A soluble activin receptor type IIb prevents the effects of androgen deprivation on body composition and bone health. Endocrinology. 2010;151(9):4289-4300.

6. Cadena SM, Tomkinson KN, Monnell TE, et al. Administration of a soluble activin type IIB receptor promotes skeletal muscle growth independent of fiber type. Journal of applied physiology (Bethesda, Md. : 1985). 2010;109(3):635-642.