with it now looking like it doesnt affect / bind to heart receptors - Id suspect we may even see people take this in as little as next year? Strength doesnt seem to go up - but size did.
MYOSTATIN UPDATE
The First Human Trials For Myostatin Released!
Earlier this month, the first human trials for myostatin inhibitors were published, revealing promising results. The study examined the effects of MYO-029, which is a recombinant human antibody that binds with a high affinity to myostatin and inhibits its activity.3 This myostatin-neutralizing antibody has previously been shown to increase muscle mass in mice by approximately 30 percent over three months.4 The study enrolled 136 subjects with various forms of muscular dystrophy. The subjects were randomized to three groups of MYO-029 dose escalation: group 1 received 1mg/kg; group 2 received 3mg/kg; and group 3 received 10mg/kg. Within each cohort, subjects were randomly assigned to receive the test drug or placebo. MYO-029 was administered intravenously every two weeks for six months (total of 13 doses). After the last dose, subjects were followed for three months. In this first-ever study of a myostatin inhibitor, the primary objective was safety. MYO-029 was well tolerated in the group of people with muscular dystrophies. No target-related side effects were identified to skeletal, smooth, or cardiac muscle. The most significant adverse events reported were skin reactions. Muscle mass was found to increase by approximately 2.4 percent in the 3mg/kg cohort; additionally there was a dose-dependent increase in fiber diameter in the 3 and 10mg/kg groups. The disappointing result of the study was that there were no increases in strength by the myostatin inhibitor. The myostatin drug seemed to have good tolerability at lower dosages, but at higher dosages many subjects experienced adverse skin reactions. The most exciting aspect of the study was that there were no adverse effects on the heart!
Myostatin Gene Deletion Prevents Glucocorticoid Induced Muscle Atrophy
Just about all muscle-wasting diseases have an increase in myostatin activity. The muscle atrophy resulting from catabolic factors, such as glucocorticoids, starvation and illness, could be the result of inhibition of protein synthesis or stimulation of protein breakdown in skeletal muscle. Glucocorticoids are steroid-based and possess anti-inflammatory and immunosuppressive properties. Glucocorticoids are normally produced normally by the adrenal cortex and provide for the response to stress. Dexamethasone is a glucocorticoid commonly used for the treatment of a vast array of diseases such as chronic inflammatory disease, lupus and rheumatoid arthritis. Dexamethasone is highly catabolic and long-term use causes muscle atrophy in humans and animals alike. There is a dose-dependent increase in myostatin mRNA, which coincides with decreases in myosin-heavy chain protein (i.e., a protein found in muscle fibers that is involved in muscle contraction) expression when dexamethasone is administered.5 To be precise, a single dose of dexamethasone caused a 60 percent (4 hours after) and a 270 percent (24 hours later) increase in myostatin mRNA expression in muscle.6 This suggests that the muscle-wasting effects of dexamethasone are mediated by an upregulation of the myostatin gene.
Researchers from France examined the effects of glucocorticoids on myostatin-deficient mice. They administered low and high dosages of glucocorticoids to myostatin-deficient mice and normal mice and examined changes in muscle mass. They found that myostatin gene deletion prevents the skeletal muscle atrophy caused by glucocorticoids. Thus, glucocorticoid administration decreased the muscle weight, muscle fiber CSA and myofibrillar protein content In Control mice, whereas these catabolic effects were not observed in myostatin-deficient mice.7 It’s amazing that even when myostatin mice are given highly catabolic drugs, they still don’t lose muscle mass! Think about the advantages of never losing muscle mass when trying to get ripped up for a show…where can we get this stuff?
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MYOSTATIN UPDATE
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Long-Term Enhancement Of Skeletal Muscle Mass And Strength By Single Gene Administration Of Myostatin Inhibitors
Let’s just say you can’t wait for FDA approval of myostatin and you were to put on your black ski mask and “Mission Impossible” suit and break into a top-secret medical facility and escape with a single vial of myostatin gene inhibitor syringe. What kind of gains would you expect? Well, researchers examined the effect of a single dose of myostatin gene inhibitors on muscle and strength gains in mice. All animals treated with the myostatin inhibitors demonstrated an increase in body mass, with an observable gross enhancement of muscles when analyzed two years later compared with treated controls. The enlarged muscle mass was accompanied by functional improvement demonstrated by an increase in hindlimb grip strength. There was no effect on heart mass or histological appearance of cardiomyocytes, indicating that myostatin inhibition was selective to skeletal muscle tissue. Effects were not restricted to the injected muscles; they were also found at sites remote from directly targeted muscles. Increased muscle mass translated to a dose-dependent improvement in muscle strength in the hindlimbs and forelimbs of treated animals compared with treated controls.14 So even a single dose of myostatin inhibitors is shown to have substantial gains in mass and in strength; this means weekly injectables of anabolics may not be necessary if myostatin-inhibiting drugs proves safe in humans. Remember, the mice are not exercising…they are just sitting around eating, yet they have gross muscle enhancement and increased strength.
Myostatin Increases Muscle Mass, But Causes Weak Tendons
Myostatin has a well-characterized role in the regulation of skeletal muscle mass, but less is known about the effects on tendons. It has been hypothesized that myostatin causes the muscles to grow faster than the tendons, which can lead to injury. In this month’s journal of the Proceedings of the National Academy of Sciences, it was reported that myostatin-deficient mice resulted in small, brittle tendons. One of the most striking differences was that myostatin-deficient mice had a 14-fold increase in the stiffness of tendons. The stiffness of tendons is a critical factor in determining the damage to muscle fibers during contractions. So this may mean that myostatin-lowering drugs may make athletes and bodybuilders more susceptible to injuries.
Most animals that are myostatin-deficient are stronger than their normal counterparts, yet many reports have never found injuries. For example, whippet dogs that carry mutations of the myostatin gene are faster than regular whippet dogs.13 They have increased speed for short duration, but have reduced endurance capacity. The owners of whippet myostatin dogs report that they are completely healthy, with the exemption of muscle cramping in the shoulder and thigh. Additionally, in 2004, in the New England Journal of Medicine, researchers documented a child who was born with a complete myostatin deficiency; his weight was in the 75th percentile and demonstrated extreme muscularity and low body fat. Several family members of the child have been reported to be “unusually” strong. At the age of 4.5 years, the child was able to grow in muscle size and strength and could hold a 3kg dumbbell in the horizontal position with his arms extended!! At the age of 10, the cross-sectional area of his quadriceps was 7.2 times greater than boys his age! Flex Wheeler, who also has a myostatin gene mutation, remained injury-free during his competitive bodybuilding career. This is just one study in mice, but something to keep in perspective.
In the past, IGF-1 was considered the Holy Grail for increasing muscle mass; however, IGF-1 can carry cardiovascular risk factors.9,10 Myostatin is an ideal target for increasing muscle mass for several reasons: myostatin signaling is muscle specific; myostatin is secreted and can be targeted extracellularly; there are physiological inhibitor molecules of myostatin signaling (for example, follistatin); and a lack of myostatin causes hypertrophy in human beings with no apparent side effects. It is noteworthy that all the studies have reported that systemic myostatin inhibition did not cause cardiac hypertrophy despite skeletal muscle hypertrophy. This is an important safety factor for the inhibition of myostatin, either by gene therapy or by protein and antibody therapy, because cardiac hypertrophy is a highly unwanted risk factor. The recent study in humans reported that the myostatin antibody was well tolerated, with minimal side effects. Myostatin-lowering drugs are definitely the next big thing to change bodybuilding.
References:
1. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature, 1997 May 1;387(6628):83-90.
2. Wagner KR, Fleckenstein JL, Amato AA, Barohn RJ, Bushby K, Escolar DM, Flanigan KM, Pestronk A, Tawil R, Wolfe GI, Eagle M, Florence JM, King WM, Pandya S, Straub V, Juneau P, Meyers K, Csimma C, Araujo T, Allen R, Parsons SA, Wozney JM, Lavallie ER, Mendell JR. A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol, 2008 Mar 11.
3. Girgenrath S, Song K, Whittemore LA. Loss of myostatin expression alters fiber-type distribution and expression of myosin heavy chain isoforms in slow- and fast-type skeletal muscle. Muscle Nerve, 2005; 31: 34-40.
4. Whittemore LA, Song K, Li X, et al. Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. Biochem Biophys Res Commun, 2003; 300: 965-971.
5. Ma K, Mallidis C, Bhasin S, Mahabadi V, Artaza J, Gonzalez-Cadavid N, Arias J, Salehian B. Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression. Am J Physiol Endocrinol Metab, 2003 Aug;285(2):E363-71.
6. Lang CH, Silvis C, Nystrom G, Frost RA. Regulation of myostatin by glucocorticoids after thermal injury. FASEB J, 2001 Aug;15(10):1807-9.
7. Gilson H, Schakman O, Combaret L, Lause P, Grobet L, Attaix D, Ketelslegers JM, Thissen JP. Myostatin gene deletion prevents glucocorticoid-induced muscle atrophy. Endocrinology, 2007 Jan;148(1):452-60. Epub 2006 Oct 12.
8. Dennis RA, Przybyla B, Gurley C, Kortebein PM, Simpson P, Sullivan DH, Peterson CA. Aging alters gene expression of growth and remodeling factors in human skeletal muscle both at rest and in response to acute resistance exercise. Physiol Genomics, 2008 Feb 19;32(3):393-400. Epub 2007 Dec 11.
9. MCMullen JR and Izumo S. (2006). Role of the insulin-like growth factor 1 (IGF1)/phosphoinositide-3-kinase (PI3K) pathway mediating physiological cardiac hypertrophy. Novartis Found Symp, 274, 90–111; discussion 111–117, 152–115, 272–116.
10. Neri Serneri GG, Boddi M, Modesti PA, Cecioni I, Coppo M, Padeletti L, MichelucciI A, Colella A and Galanti G. (2001). Increased cardiac sympathetic activity and insulin-like growth factor-1 formation are associated with physiological hypertrophy in athletes. Circ Res, 89, 977–982.
11. Gustin P, Bakima M, Art T, Lekeux P, Lomba F, Van de Woestijne KP. Pulmonary function values and growth in Belgian white and blue doublemuscled cattle. Res Vet Sci, 1988a: 45: 405–410.
12. Gustin P, Dhem AR, Lomba F, Lekeux P. Cardio-pulmonary function values in double-muscled cattle during muscular exercise. Vet Res Commun, 1988b: 12: 407–416.
13. Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS, Parker HG, Ostrander EA. A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genet, 2007 May 25;3(5):e79.
14. Haidet AM, Rizo L, Handy C, Umapathi P, Eagle A, Shilling C, Boue D, Martin PT, Sahenk Z, Mendell JR, Kaspar BK. Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors. Proc Natl Acad Sci USA, 2008 Mar 18;105(11):4318-22.
