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December 2015

  1. ACE-031: Not Just a Myostatin Inhibitor(?)

    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.
  2. 176-191 and its Potential in Lipolysis, Growth and Development

    The effects of genetic GRF knock-out on the growth and body composition of mice (KO) compared with that of normal healthy controls. From Sun LY, Spong A, Swindell WR, et al., Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. eLife. 2013;2:e01098, reproduced under the terms of the Creative Commons Attribution License

    The effects of genetic GRF knock-out on the growth and body composition of mice (KO) compared with that of normal healthy controls. From Sun LY, Spong A, Swindell WR, et al., Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. eLife. 2013;2:e01098, reproduced under the terms of the Creative Commons Attribution License

    176-191 is the common term for a fragment of human growth hormone (hGH). It is often regarded as a mimic of the C-terminus of hGH; in other words, it is a peptide made up of the last 16 amino acids found in the sequence of the hormone. This region of hGH has been linked to the reduction of fat and fat tissue in mammals, by promoting lipolysis and inhibiting lipogenesis1. However, this fragment of hGH has also been associated with the inhibition of insulin, and thus increased risks of hyperglycaemia2. These effects may be related to amino acids 178 to 190 in the hGH sequence2. Conversely, the amino-terminus of hGH has been found to have a significant effect on glucose breakdown mediated by insulin in healthy rats3. Animal studies investigating the properties of a 177-191 fragment have found that this peptide may disrupt the regulation of glycogen synthase in vivo4. This may lead to altered levels of circulating glucose. When the 176th amino acid is added to this fragment, however, it becomes an analog of the growth-hormone releasing factor (GRF). This peptide, as the name suggests, plays a role in the regulation of GH release, and is also known as growth hormone releasing hormone (GHRH)5. GRF has demonstrated the ability to significantly increase plasma GH levels and growth, as observed in young female buffalo treated with this peptide, compared to controls6. Other researchers have claimed that chronic GRF administration also resulted in significant increases in the concentrations of luteinizing hormone (LH) and progesterone in similar animals6. GRF may also be associated with reductions in dyslipidemia (impaired lipid metabolism leading to the increased accumulation of body fat)7. Based on findings such as these, some scientists argue that GRF analogs may be useful in the promotion of body weight and improved body composition in livestock and other commercially-viable animals8. Other functions of 176-191 GRF and its analogs are associated with the release of GH, and possibly IGsF, in many animals9. The release of GRF is historically associated with the hypothalamus, but has been detected in other sources, including the gonads and placenta9. As a result, some researchers propose that it has a role in fetal development9. GRF is also found in leukocytes9. Therefore, it may also have a role in the immune response and/or the regulation of the immune system.  GRF and Neurons  GRF is released by a population of neurons in the hypothalamus and anterior pituitary of many animals10. Therefore, it can also be categorized as a neuropeptide, or a protein fragment that may also act as a neurotransmitter or other type of mediator between nerve cells. A recent imaging study using rat brains found that up to 30% of the GRF neurons in this region could take up radiolabeled estradiol10. This indicates that estradiol may have a role in stimulating GRF release, and thus in the control of GH production in turn. These findings may also further clarify the as-yet uncertain role of estradiol in the central nervous system. GRF and similar peptides may also alleviate the effects of hypoxia in murine CNS studies11. References: 1. Wu Z, Ng FM. Antilipogenic action of synthetic C-terminal sequence 177-191 of human growth hormone. Biochemistry and molecular biology international. 1993;30(1):187-196. 2. Wade JD, Ng FM, Bornstein J, Pullin CO, Pearce JS. Effect of C-terminal chain shortening on the insulin-antagonistic activity of human growth hormone 177--191. Acta endocrinologica. 1982;101(1):10-14. 3. Mondon CE, Reaven GM, Ling N, Lewis UJ, Frigeri LG. Amino-terminal peptide of growth hormone enhances insulin action in normal rats. Endocrinology. 1988;123(2):827-833. 4. Macaulay SL, Armstrong JM, Bornstein J. Regulation of glycogen synthase activity in muscle by a C-terminal part sequence of human growth hormone. Archives of biochemistry and biophysics. 1983;224(1):365-371. 5. Mangili A, Falutz J, Mamputu J-C, Stepanians M, Hayward B. Predictors of Treatment Response to Tesamorelin, a Growth Hormone-Releasing Factor Analog, in HIV-Infected Patients with Excess Abdominal Fat. PLoS ONE. 2015;10(10):e0140358. 6. Haldar A, Prakash BS. Effects of growth hormone-releasing factor on growth hormone response, growth and feed conversion efficiency in buffalo heifers (Bubalus bubalis). Veterinary journal (London, England : 1997). 2007;174(2):384-389. 7. Hu M, Tomlinson B. Growth hormone-releasing factor agonists for the treatment of HIV-associated lipodystrophy. Current opinion in investigational drugs (London, England : 2000). 2010;11(10):1143-1150. 8. Sun LY, Spong A, Swindell WR, et al. Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. eLife. 2013;2:e01098. 9. Campbell RM, Scanes CG. Evolution of the growth hormone-releasing factor (GRF) family of peptides. Growth regulation. 1992;2(4):175-191. 10. Shirasu K, Stumpf WE, Sar M. Evidence for direct action of estradiol on growth hormone-releasing factor (GRF) in rat hypothalamus: localization of [3H]estradiol in GRF neurons. Endocrinology. 1990;127(1):344-349. 11. Nair D, Ramesh V, Li RC, Schally AV, Gozal D. Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse. Journal of neurochemistry. 2013;127(4):531-540.

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