Unlimited Muscle Growth – The Myostatin Factor

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Unlimited Muscle Growth – The Myostatin Factor

Foreword by Andrew Carruthers, Editor-In-Chief. Article By Ian Roothman, BSc (M Biochem)(Phys) MCSD

For the average person on the street, seeing a huge bodybuilder is something that really catches their attention. But once you’ve been in the game long enough and you’ve seen bodybuilders on a daily basis, you become de-sensitized by size – that is until someone posts a photo-shopped version of a human with immense and over dramatic size and the question which then starts to run around your mind is why. Why can’t the human muscular system get that big? What’s stopping humans from growing to sizes that are uncomprehending? The answer might just lie in the Myostatin Factor.

Myostatin is a protein that acts as a muscle-growth inhibitor. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood and acts on muscle tissue by binding to a cell-bound receptor called the activin type-II receptor. It has been a hot topic in the supplement industry for a while now, with substantial information on it available on the Internet. However the only real scientific evidence on this protein can only be found in research papers buried deep in the archives of scientific journals. In theory, successfully inhibiting myostatin may lead to unlimited muscle growth, but there are a few important aspects that have to be taken into account regarding this scenario.

Regulating Myostatin Bioactivity

By regulating myostatin bioactivity the signal for muscle growth can, in theory, be turned on and off. There are natural sulfated polysaccharides (SP) derived from brown seaweed that comprise a complex group of macromolecules with a wide range of important physiological properties. Examples of other polysaccharides include storage polysaccharides, such as starch and glycogen, and structural polysaccharides like cellulose and chitin. However, the sulfated version of these molecules have been shown to bind and directly regulate the bio-activity of growth factors and cytokines, such as basic fibroblast growth factor, interferon, various enzymes and transforming growth factor. Myostatin is a member of the transforming growth factor-beta (TGF-beta) family that acts as a negative regulator of skeletal muscle mass. It has been demonstrated in research studies that SPs isolated from the brown seaweed Cystoseira Canariensis bind to the myostatin protein in serum.

Recent studies have shown that myostatin may also be involved in the formation of fibrosis (the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process) within skeletal muscle. In this study biochemists further explored the potential role of myostatin in skeletal muscle fibrosis, as well as its interaction with both transforming growth factor-beta1 and decorin (a small leucine-rich proteoglycan). It was discovered that myostatin stimulated fibroblast proliferation in vitro and induced its differentiation into myofibroblasts. Furthermore, it was found that transforming growth factor-beta1 stimulated myostatin expression and, conversely, myostatin stimulated transforming growth factor-beta1 secretion in C2C12 myoblasts. Decorin was found to neutralise the effects of myostatin in both fibroblasts and myoblasts and also up-regulated the expression of follistatin, the antagonist of myostatin.

Research note: In Vivo: Experimentation “within the living” – using a whole, living organism as opposed to a partial or dead organism
In Vitro: Experimentation within glass – not performed in a living organism but in a controlled environment

The results of in vivo experiments showed that myostatin knock-out mice developed significantly less fibrosis and displayed better skeletal muscle regeneration when compared with wild-type mice at two and four weeks following gastrocnemius (calf) muscle laceration injury. In the wild-type mice transforming growth factor-beta1 and myostatin co-localised in myofibres in the early stages of injury. Synthesised myostatin protein stimulated myofibres to express transforming growth factor-beta1 in skeletal muscles at early points following injection. In summary, these findings define a fibrogenic property of myostatin and suggests the existence of co-regulatory relationships between transforming growth factor-beta1, myostatin and a small leucine-rich protein that is heavily glycosylated (an enzymatic process where poly- or oligosaccharides are attached to proteins), called decorin.

Decorin was found to play an important role in the regulation of cell growth. Recent studies have shown that immobilised decorin in the collagen matrix sequesters myostatin into the extracellular matrix and prevents its inhibitory action to myoblast proliferation in vitro. However, it still remains unclear whether free decorin could affect the proliferation and differentiation of myogenic cells by regulating myostatin activity. It was showed that decorin over-expressing cells had an increased rate of proliferation as compared to control cells. Decorin over-expressing cells formed multi-giant hypertrophic myotubes with an elongated morphology and larger size – which means increased muscle size. Consistent with these results, knock-down of decorin impairs myoblast growth by increasing the sensitivity to exogenous myostatin. These results clearly show that decorin enhances the proliferation and differentiation of myoblasts by suppressing myostatin activity and thus enhances muscle cell growth.

Anabolic Steroids

Although in vivo and in vitro studies have established that anabolic steroids, transforming growth factor-beta (TGF-beta) and myostatin affect muscle growth in meat-producing animals, their mechanisms of interaction are not completely understood. Anabolic steroids have been widely used as growth promoters in feedlot cattle for over 50 years. A growing body of evidence suggests that increased muscle levels of IGF-I and increased muscle satellite cell numbers play a role in anabolic steroid enhanced muscle growth. In contrast to anabolic steroids, the members of the TGF-beta-myostatin family suppress muscle growth in vivo and suppress both proliferation and differentiation of cultured myogenic cells. Recent evidence suggests that IGF plays a role in mediating the proliferation-suppressing actions of both TGF-beta and myostatin on cultured myogenic cells. Consequently, future research studies will review the roles of IGF-I in the cellular and molecular mechanisms of anabolic steroids and TGF-beta and myostatin, respectively.

Muscle Cell Growth

The superfamily of transforming growth factor-beta (TGF-beta) cytokines have been shown to have profound effects on cellular proliferation, differentiation and growth. Recently there have been major advances in our understanding of the signaling pathway(s) conveying TGF-beta signals to the nucleus to ultimately control gene expression. One tissue that is potently influenced by TGF-beta superfamily signaling is skeletal muscle. Skeletal muscle ontogeny and postnatal physiology have proven to be exquisitely sensitive to the TGF-beta superfamily cytokine milieu in various animal systems, including humans. Recently, major strides have been made in understanding the role of TGF-beta and its closely related family member, myostatin, in these processes. By studying the latest journals we have found recent advances in our understanding of the TGF-beta and myostatin signaling pathways and, in particular, focus on the implications of this signaling pathway for skeletal muscle development, physiology and pathology.

Growth Hormone

Growth hormone continues to be both the most promising and the most controversial fat loss and anti-catabolic hormone therapy. A recent study achieved spectacular results, including a 21% loss of body fat in men when growth hormone was combined with testosterone. However, because of the serious side effects most studies are opposed to growth hormone replacement as it is currently administered and most are waiting for more developments in the field of growth hormone releasers before continuing research. Myostatin’s inhibitory actions on striated muscle growth are believed to be directly mediated by locally produced myostatin and possibly by IGF binding proteins. Therefore, in these studies, skeletal muscle, heart and liver expression in neonates and adults were measured. Myostatin receptors, but not myostatin itself, are expressed in the liver, so changes in the hepatic production of circulating IGF axis components could therefore result from the loss of endocrine myostatin. Thus, myostatin may inhibit striated muscle growth directly at the cellular level and indirectly through systemic effects on the IGF axis. The development of effective growth hormone releasers, which could maintain growth hormone at youthful physiological levels, appears to be of great importance. We now know that growth hormone receptors exist in the brain and that growth hormone stimulates neurogenesis (the production of new nerve cells). In addition, growth hormone has a tremendous impact on sexual function, sleep, the maintenance of lean body mass and the prevention of obesity.

12 Week Resistance Training

Research studies examined 12 weeks of resistance training and cystoseira canariensis supplementation on serum levels of myostatin and follistatin-like related genes (FLRG), as well as muscle strength and body composition. Twenty-two untrained males were randomly assigned to a placebo (PLC) or myostatin binder (MYO) group in a double-blind fashion. Blood was obtained before and after 6 and 12 weeks of training. PLC and MYO trained three times weekly using three sets of 6-8 repetitions at 85-90% of one rep maximum. MYO ingested 1200mg/d of cystoseira canariensis. Data were analyzed after training – total body mass, fat-free mass, muscle strength, thigh volume/mass, serum myostatin and FLRG increased for both groups. According to this study 12 weeks of heavy resistance training and 1200 mg/d of cystoseira canariensis supplementation appears ineffective at inhibiting serum myostatin and increasing muscle strength and mass or decreasing fat mass.

Testosterone

Recent studies on testosterone confirmed its impact on muscle growth. Part of testosterone’s mechanism of action could be anti-glucocorticoid. As glucocorticoids up-regulate the production of myostatin it was found that testosterone reverses this effect.

HMB

Beta-hydroxy-beta-methylbutyrate (HMβ) is a metabolite of leucine, widely used for improving sports performance. Although HMβ is recognised to promote anabolic or anti-catabolic effects on protein metabolism, the impact of its long-term use on skeletal muscle and/or genes that control the skeletal protein balance is not fully known. It was speculated that HMB might have an effect on myostatin bioactivity. Future research is aimed at investigating the exact method of how and whether chronic HMβ treatment affects the activity of GH/IGF-I axis, skeletal muscle IGF-I and myostatin bioactivity. However, in recent studies, chronic HMβ treatment increased the content of pituitary Growth Hormone (GH) mRNA and GH, hepatic IGF-I production and serum IGF-I concentration. No changes were detected on skeletal muscle IGF-I and myostatin production. The results presented in these studies extend the body of evidence on the potential role of HMβ-supplementation in stimulating GH/IGF-I axis activity. In spite of this effect, HMβ supplementation also induces an apparent state of insulin resistance, which might limit the beneficial aspects of the GH stimulating effect.

Conclusion

Looking at all the scientific evidence it can be concluded that myostatin plays an important role in recovery and muscle growth. There are various aspects and scientific controversy surrounding this much exploited protein, but it should be a topic to be taken note of by all athletes interested in sports, especially bodybuilding and other power sports where muscle size enhancement is of utmost importance. However, future research is required to determine the effect of how supplementation may be used to optimally suppress and counteract the muscle growth inhibitory effect of the myostatin factor.

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