Inhibition of myostatin as a potential therapeutic agent for muscular dystrophy was first investigated in mdx mice, which has a premature stop codon in the dystrophin gene and is therefore a model of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (DMD) [20]. Mdx mice lacking myostatin had increased myofiber size with increased muscle weight, improved grip strength, and reduced fibrosis compared to their MDX counterparts [21]. Studies with postnatal myostatin inhibitors in MDX have also shown increased muscle weight and strength in decreased fibrosis [17,22–▪ 26]. However, in none of these studies did the degree of increase in muscle strength reflect the degree of muscle hypertrophy. It was also feared that, in many physiological studies, the absolute strength of isolated muscles increased with myostatin inhibition, but not the specific strength (cross-sectional force). The clinical relevance of specific versus absolute strength is unclear. But the first question that might come to mind is, how much natural myostatin suppression is enough to see results? When we look at studies on muscle breakdown, we see a good indication of the types of changes in serum myostatin that are important. In particular, a study published in 1999 showed that a plasma increase of only 12% in myostatin corresponded to a staggering average loss of 2.2 kilograms of lean skeletal muscle mass over 25 days. If a little safe extrapolation is allowed, a decrease in myostatin of only 12% should be enough to stimulate clinically significant muscle gain.
However, there are several potential disadvantages of myostatin inhibition in people seeking athletic improvement. Physiologically, minimal amounts of cardiac myostatin are secreted from the myocardium into the serum, which has a limited effect on muscle growth. [62] However, an increase in cardiac myostatin can increase serum concentration, which can lead to skeletal muscle wasting. [61] [62] Pathological conditions that increase cardiac stress and promote heart failure may induce increased levels of mRNA and cardiac myostatin proteins in the heart. [61] [62] In ischemic or dilated cardiomyopathy, elevated levels of myostatin mRNA in the left ventricle have been detected. [61] [66] Ultimately, it was debulking and natural processing to produce a powder through a high-quality handling technique that truly produced the very first clinically tested natural myostatin inhibitor of its kind, MYO-T12 (currently available from MHP as MYO-X, a breakthrough in the science of body transformation). In 2009, I published results confirming that the active ingredients in this fertile egg isolate were not only absorbed and active in humans, but also resulted in a temporary decrease in mean serum myostatin of 46% on average over 12 hours in all study participants. A case study of a human child with abnormally high muscle development reported that the child also had very low levels of myostatin. The authors suggested that myostatin inhibition may have been involved in the observed increase in muscle growth, although no other similar cases have been reported [18]. Blastodisc research for fertile eggs produced the first natural, non-pharmaceutical and now widely used myostatin inhibitor. While the research I published in 2006 found that fertile chicken eggs did contain biologically active follistatin, it was my work on the first human pilot study looking at hormone absorption and influences that really set the stage for further studies.
Research studies have examined fortetropin and its potential to reduce myostatin or affect muscle growth, including one published in the Journal of the International Society of Sports Nutrition titled “The Effects of a Myostatin Inhibitor on Lean Body Mass, Strength, and Strength in Resistance Trained Men.” This study notes that myo-T12 is “follistatin derived from fertile chicken egg yolk isolate.” A fact sheet available from the company Myos Rens, which owns fortetropin, states that it “reduces free serum myostatin® levels”. This fact sheet hints at a medium-term opportunity when the ingredient could be used as a medicinal food for the dietary treatment of sarcopenia and cachexia, ® conditions that lead to muscle loss. Despite the lack of evidence, some companies claim that their exercise supplements also act as myostatin inhibitors. First, take a look at the language used in the AMA`s Prohibited List of Myostatin Inhibitors. Myostatin inhibitors are included in the primary category “S4 hormone and metabolic modulators”. The 2018 WADA Prohibited List wording for Standard S4.4 reads: “Agents that alter the function(s) of myostatin, including but not limited to: myostatin inhibitors.” The new expanded wording of WADA`s 2019 Prohibited List under S4.4 is set out below. This article will review the preclinical promise of myostatin inhibitors, the experience of clinical trials of these inhibitors in muscular dystrophy, and possible reasons for the observed lack of translation. The key is strength training in the right way to stimulate myostatin suppression. As soon as training is difficult enough for the muscle, the recovery phase begins, which is initiated by a drop in myostatin. This temporary natural drop in myostatin repairs muscles and, if the stimulus is intense enough, leads to an increase in muscle size in anticipation of another similar workload. A study published in 2004 found that healthy male subjects who completed intense resistance training had a 20% decrease in serum myostatin, resulting in a 30% increase in strength and a 12% increase in muscle mass over 10 weeks of training. In terms of muscle building, anything that lowers serum myostatin below 20% of baseline is likely to result in clinically significant muscle gains.
In mature muscle, myostatin inhibits Akt, a kinase sufficient to cause muscle hypertrophy, in part by activating protein synthesis while stimulating the production of ubiquitin ligases, proteins that regulate muscle protein breakdown. However, Akt is not responsible for all observed hyperthrophic muscle effects mediated by myostatin inhibition. [20] Myostatin therefore acts in two ways: by inhibiting act-induced protein synthesis and by stimulating ubiquitin-regulated protein degradation. Consider the following possible clarifications in relation to mysotatin inhibitors. Adding the word “pharmaceuticals” before myostatin inhibitors and agents that reduce or absolve myostatin expression would make it clear that the category refers to drugs and not food. If follistatin AAV1-FS344 injections are the target, why not clarify with one of the following injections: “follistatin AAV1-FS344” or “follistatin injections”. Athletes and bodybuilders have been fascinated by myostatin since it was discovered in the 1990s by a Johns Hopkins researcher named Se-Jin Lee. If you visit Lee`s mouse lab, you can see why the discovery attracted so much attention. Research has spawned several muscle-strengthening drugs that are now being tested in people with medical conditions, including muscular dystrophy, cancer and kidney disease. The drugs all work by blocking a substance called myostatin, which the body normally produces to prevent muscles from getting too big.
Animals that lack myostatin or animals that have been treated with substances such as follistatin, which block the binding of myostatin to its receptor, have much larger muscles. Therefore, reducing myostatin could potentially benefit livestock farming, with even a 20% reduction in myostatin levels potentially having a big impact on muscle development. [27] The dystrophin-free Golden Retriever Muscular Dystrophy Dog Model (GRMD) has a more severe phenotype than the MDX mouse and has muscular expression values of myostatin similar to those of human DMD, on average 15% of normal dogs [56]. A study of genetic loss of myostatin in the GRMD model was of concern for disproportionate muscle growth, increased joint contractures, and lack of statistically significant changes in GRMD strength without myostatin [57].
