Miostatina e crescimento muscular

Eu não vou ficar explicando o que é Miostatina. Segundo a Wikipedia (http://pt.wikipedia.org/wiki/Miostatina)

😉 :

Miostatina

Origem: Wikipédia, a enciclopédia livre.

miostatina (formalmente conhecida como factor 8 de crescimento e diferenciação) é um fator de crescimento que limita o crescimento do tecido muscular, por exemplo concentrações elevadas de miostatina em um indivíduo provocam uma diminuição no desenvolvimento normal dos músculos.[1]

A proteína miostatina é produzida em células do músculo esquelético, circula no sangue e actua no tecido muscular, parecendo atrasar o desenvolvimento das “células-mãe” musculares. O mecanismo exato segue sendo desconhecido.

Miostatina e o gen associado foram descobertos 1997 pelos genetistas McPherron e Se-Jin Lee, que também produziram uma estirpe do mutante em ratos com a carência do gen e eram em torno de duas vezes mais fortes que ratos normais. [1] [2]

O gen foi sequenciado em humanos, ratos, peixes, zebras e vários outro animais,[3] demonstrando poucas diferenças entre espécies. Lee descobriu em 1997 que a raça bovina “Azul Belga Forte” e uma camada de Piedmontese tinham o gen da Miostatina defeituoso. Essas linhagens se produziram através de criação de gado.(fonte: http//www.pharyngula.org)

Em 2001, Lee cria ratos com o gen da Miostatina intacto e uma grande massa muscular inserindo mutações que aumentaram a produção de substâncias bloqueadoras da Miostattina.[4][5][6]
Em 2004, um sujeito alemão foi diagnosticado com uma mutação em ambas as cópias do Gen que produz a Miostatina, fazendo-o consideravelmente mais forte que seus pais. Sua mãe possuia mutação em uma das cópias do gen.[7][8][9][10][11][12] Mais recentemente, um garoto americano nascido em 2005 foi diagnosticado com a mesma condição.[13]

Investigações adicionais na Miostatina e o gen da miostatina pode conduzir a terapias para a distrofia muscular. A idéia é introduzir substâncias que bloqueiam a miostatina. Em 2002, investigadores da Universidade da Pennsylvania demonstraram que com um anticorpo monocloral específico para a Miostatina melhora a condição de ratos com distrofia muscular, provavelmente mediante o bloqueio da ação da Miostatina.

Em 2005, Lee demostrou que com um tratamento de duas semanas a ratos normais com o receptor da activita tipo 11B soluvel, una molécula que se une normalmente as células e a Miostatina, conduz a um aumento notável na massa muscular (até 60%). Se pensa que a união da Miostatina com o receptor solúvel impede que ela se una ao receptor da superfície celular.

Continua confuso se um tratamento longo da distrofia muscular com os inibidores da Miostatina é benéfico: O esgotamento das células-mãe musculares poderia piorar a doença a longo prazo.

Até 2005, não existem remédios no mercado para os seres humanos, mas foi desenvolvido um anticorpo genéticamente modificado para reconhecer a Miostatina e neutralizá-la pela companhia farmacêutica de Nova Jersey Wyeth. O inibidor se chama MYO-029 e está atualmente em fase experimental em humanos. Alguns atletas, impacientes para conseguir esses medicamentos, procuram pela internet, onde estão vendendo bloqueadores de Miostatina falsos.

A Miostatina é um membro da superfamilia de proteínas TGF-beta. A Miostatina humana consiste em duas subunidades idênticas, cada uma consistindo de 110 aminoácidos. Seu peso molecular total é de 25.0 kDa. Pode ser produzido por “E. coli” modificada geneticamente e esta disponível para venda. A Universidade de Johns Hopkins possui as patentes da miostatina.

[editar]Ver também

Segundao a comunidade FAM(Fanaticos Academia Musculaçao)

[editar]Referências

  1.  Garikipati DK, Gahr SA, Roalson EH, Rodgers BD. “Characterization of rainbow trout myostatin-2 genes (rtMSTN-2a and -2b): genomic organization, differential expression, and pseudogenization.” Endocrinology 2007;148(5):2106-15. PMID 17289851.
  2.  McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997;387:83-90. PMID 9139826.
  3.  Rodgers e Weber. “A conservação sequencial entre a miostatina ortológica dos peixes e a caracterização de dois clones cDNA adicionais de Morone saxatilis e Morone Americana” Comp Biochem Physiol B Biochem Mol Biol 2001;129(2-3):597-603. PMID 11399495.
  4.  Fotos com dupla musculatura por Miostatina inibida en touros Azul Belga
  5.  Kambadur R, Sharma M, Smith T, Bass J (1997). “Mutaciones en miostatina (GDF8) de ganado doble musculados Azul Belga y Piedmontese”. Genome Res 7 (9): 910-6. PMID 9314496.
  6.  McPherron A, Lee S (1997). “Doble musculación en ganado debido a mutaciones en el gen miostatina”. Proc Natl Acad Sci U S A 94 (23): 12457-61. PMID 9356471.
  7.  cevgenetica: Mutación Génica hace a sujeto alemán extra muscularmente fuerte
  8.  Gina Kolota: Un niño muy muscular ofrece esperanza contra enfermedades, The New York Times, June 24, 2004. (requiere login)
  9.  Mutación genética hace un superboy
  10.  Pibe Músculo
  11.  One Strong Tyke: Gene mutation in muscular boy may hold disease clues
  12.  Schuelke M, Wagner K, Stolz L, Hübner C, Riebel T, Kömen W, Braun T, Tobin J, Lee S (2004). “Mutación en miostatina asociada con hipertrofia muscular en un niño”. N Engl J Med 350 (26): 2682-8. PMID 15215484.
  13.  “Rare condition gives toddler super strength”

Até aí, tranquilo… O problema, ou solução, vem agora:

Com diferentes animais já se observou que a miostatina pode modificar a massa muscular:

Com ratos (quando se bloqueia a expressão da miostatina):

Com bois (Belgian Blue) e cachorros (Whippet), que nascem com supressão da miostatina:

Com peixes (truta):

Ah, tem estudos que investigam a inserção de primers que têm a função de alterar o DNA e, por consequência, suprimir a expressão da miostatina. 

Há o exemplo que coloquei dos ratos (que mais se aproximam dos humanos), mas existe com peixe também:

Qual o lance? Esta supressão da miostatina já foi vista em um humano, que nasceu assim 😉

Há quem diga que o nome dele é Liam

Porém, outros garotos já exibiram características semelhantes, como o Richard Sandrak e o Giuliano Stroe.

O problema começa depois que eu conheci a Acceleron Pharma Inc. Ela tem quatro estudos do tipo clinical trial registrados (seja já completado, terminado ou suspenso):

http://clinicaltrials.gov/ct2/show/NCT00755638

http://clinicaltrials.gov/ct2/show/NCT01099761

http://clinicaltrials.gov/ct2/show/NCT00952887

http://clinicaltrials.gov/ct2/show/NCT01239758

Eles estão testando um fármaco chamado, por enquanto, de ACE-031.

Segundo as informações, o negócio é fera, e mexe mesmo com a massa muscular. O último artigo que eu vi publicado é com ratos, e tem como capa:

E o resumo trás as seguintes informações:

 
Cadena SM, Tomkinson KN, Monnell TE, Spaits MS, Kumar R, Underwood KW, Pearsall RS, Lachey JL. 
Administration of a soluble activin type IIB receptor promotes skeletal muscle growth independent of fiber type. 
J Appl Physiol. 2010 Sep;109(3):635-42. Epub 2010 May 13.

This is the first report that inhibition of negative regulators of skeletal muscle by a soluble form of activin type IIB receptor (ACE-031) increases muscle mass independent of fiber-type expression. This finding is distinct from the effects of selective pharmacological inhibition of myostatin (GDF-8), which predominantly targets type II fibers. In our study 8-wk-old C57BL/6 mice were treated with ACE-031 or vehicle control for 28 days. By the end of treatment, mean body weight of the ACE-031 group was 16% greater than that of the control group, and wet weights of soleus, plantaris, gastrocnemius, and extensor digitorum longus muscles increased by 33, 44, 46 and 26%, espectively (P < 0.05). Soleus fiber-type distribution was unchanged with ACE-031 administration, and mean fiber cross-sectional area increased by 22 and 28% (P < 0.05) in type I and II fibers, respectively. In the plantaris, a predominantly type II fiber muscle, mean fiber cross-sectional area increased by 57% with ACE-031 treatment. Analysis of myosin heavy chain (MHC) isoform transcripts by real-time PCR indicated no change in transcript levels in the soleus, but a decline in MHC I and IIa in the plantaris. In contrast, electrophoretic separation of total soleus and plantaris protein indicated that there was no change in the proportion of MHC isoforms in either muscle. Thus these data provide optimism that ACE-031 may be a viable therapeutic in the treatment of musculoskeletal diseases. Future studies should be undertaken to confirm that the observed effects are not age dependent or due to the relatively short study duration.

Dêem uma olhada na espessura das fibras musculares, de ratos tratados com o ACE-031:

Diferentes, não?

Aí a coisa engrossa quando a gente vê que o seguinte: um pesquisador da J Hopkins Univ (SJ Lee) publica o seguinte editorial, que basicamente fala do artigo do CADENA, supracitado.

EDITORIAL: Lee S-J. Speed and endurance: you can have it all. J Appl Physiol 2010;109(3):621-2. 

SKELETAL MUSCLE COMPRISES multiple fiber types that vary in their contractile and metabolic properties. Muscle fibers are classified primarily on the basis of the specific myosin heavy chain isoform that they express. Slow twitch or type I fibers are rich in mitochondria, rely principally on oxidative metabolism, and have a high resistance to fatigue. Fast-twitch or type II fibers are more susceptible to fatigue and come in several subtypes (IIa, IIx, and IIb); these subtypes can be distinguished not only in terms of their contractile protein isoforms, but also with respect to their metabolic properties, which range from mixed oxidative/glycolytic to predominantly glycolytic. The relative proportions of different fiber types in a given muscle are believed to affect its overall functional properties, such as power, speed, and endurance, and dysfunction of specific fiber types can accompany a variety of disease processes, including type II diabetes and age-related muscle loss or sarcopenia. As a result, there is considerable interest in developing strategies and agents capable of enhancing the functions of specific types of myofibers.

One major focus of efforts to develop drugs capable of promoting muscle growth for clinical applications is the signaling pathway regulated by myostatin (MSTN), which is a transforming growth factor-β (TGF-β) family member that normally acts to limit skeletal muscle mass (12). Genetic loss of MSTN has been shown to result in dramatic increases in muscle mass in multiple species, including humans, and inhibition of myostatin activity in adult mice has been shown to induce significant increases in muscle growth and muscle strength (for review, see Ref. 8). These and other studies have demonstrated that myostatin normally plays two roles in limiting muscle mass. One role is to regulate the number of muscle fibers that are formed during development, and several studies have shown that the increases in fiber number seen in Mstn null mice result mostly from increases in the numbers of type IIx and IIb fibers (2, 4, 6, 11). A second role of myostatin is to regulate postnatal growth of muscle fibers, and hypertrophy of type II fibers has been well documented in adult mice treated with myostatin inhibitors. The combination of increased numbers and sizes of type II fibers has been interpreted to be largely responsible for one of the striking examples of the functional consequences of myostatin loss, namely the superior racing performance of whippets that are heterozygous for a MSTN loss-of-function mutation (14). Although the major effects of blocking myostatin activity seem to be on inducing type II fiber hypertrophy, effects on type I fibers have also been reported following viral delivery of an expression construct for the myostatin propeptide, which is an inhibitor of myostatin signaling (5, 10). In this issue of the Journal of Applied Physiology, Cadena et al. (3) use a pharmacological approach to examine the role of this signaling pathway in regulating growth of different fiber types. The authors provide additional evidence that this pathway seems to function in adult mice to regulate growth of not only type II fibers, but also type I fibers.

To block myostatin activity, Cadena et al. (3) utilized a biologic called ACE-031, which is Acceleron’s version of a soluble form of the activin type IIB receptor (ACVR2B or ActRIIB). Previous studies have demonstrated that myostatin signals initially by binding to activin type II receptors and that systemic administration of a soluble form of ACVR2B, consisting of its ligand binding portion fused to an Fc domain, can cause dramatic muscle fiber hypertrophy (9). Cadena et al. (3) carried out a detailed examination of the effects of systemic administration of ACE-031 at the level of the muscle fiber. Analysis of the soleus muscle, which contains a mixture of type I and type II fibers, revealed that the total numbers of muscle fibers, as well as the total numbers of each of the individual fiber types, were similar in ACE-031-treated and control mice. The fact that overall fiber number was unchanged implied that all of the increased muscle growth induced by ACE-031 resulted from muscle fiber hypertrophy, and, consistent with previous reports, the authors found significantly increasedmuscle fiber sizes in mice treated with ACE-031. The new finding was that these increases in fiber sizes were seen both in type II and in type I fibers.

An important issue raised by these findings that warrants further investigation is the identity of the ligand being targeted by ACE-031 to induce its effect on type I fibers. Previous studies have shown that muscle growth is regulated by multiple TGF-β-related ligands that signal through activin type II receptors and that one of the reasons for the dramatic effects seen with the soluble ACVR2B receptor in terms of inducing muscle growth is that this agent is capable of blocking more than just myostatin, as demonstrated by the ability of this inhibitor to induce muscle growth even in Mstn null mice (9). Given that there is considerable debate as to whether the best pharmacological agents for clinical use will be ones that are highly specific for myostatin or ones with a broader range of ligand specificity, it will be important to determine whether these effects of ACE-031 in inducing type I fiber hypertrophy reflect inhibition of myostatin activity or that of another ligand that also signals through activin type II receptors to regulate muscle growth. An intriguing possibility is that different TGF-β-related ligands may be responsible for regulating the growth and function of different fiber types, although previous studies have demonstrated effects on type I fibers by overexpressing the myostatin propeptide (5, 10), which seems to be capable of blocking only myostatin and thehighly related ligand, GDF-11.

From the perspective of muscle as a contractile organ, the findings reported by Cadena et al. (3) are significant in that they further support the possibility that blocking this signaling pathway could lead to enhancement of not only functional parameters like strength and speed, but perhaps also those related to muscle fatigue and endurance. Moreover, these findings have potential implications for the use of myostatin inhibitors in disease settings in which type II fibers are lost, such as in age-related sarcopenia, which seems to affect type IIb fibers preferentially. In particular, the new findings suggest that myostatin inhibition may be beneficial not only for providing an anabolic stimulus to the residual type II fibers, but perhaps also for promoting the function of the type I fibers that are relatively spared in aged muscle.

From the perspective of muscle as a metabolic tissue, these findings raise additional questions regarding the metabolic effects seen when this signaling system is manipulated. Early studies showed that genetic loss of Mstn can reduce fat accumulation and improve glucose metabolism in mouse models of obesity and type II diabetes (13), and several follow-up studies have documented similar metabolic effects using pharmacological methods to block myostatin activity (1, 7). Assuming that some, if not all, of these metabolic effects result from loss of direct myostatin signaling to muscle, it will be important to understand the extent to which altered signaling in different fiber types contributed to these overall physiological effects. A major question in this regard is whether the effects of ACE-031 in inducing type I fiber hypertrophy are accompanied by corresponding effects on type I fiber metabolic activity.

From both perspectives, the findings reported by Cadena et al. (3) expand the spectrum of beneficial effects that can be seen by blocking this signaling pathway and will likely continue to fuel the optimism surrounding the targeting of this pathway for clinical applications. In this respect, at least four biotechnology and pharmaceutical companies, including Acceleron, have entered clinical trials with myostatin inhibitors in a variety of disease states. Given the wide range of clinical settings characterized by debilitating loss of muscle function, scientists, physicians, and patients will all be eagerly awaiting the results of these trials.

O lance é que o Lee recebe suporte da Metamorphix, Inc:

E, então, a gente descobre que o cara, Dr. Lee:

Dr. Lee has created a gene therapy technique that introduces a potent myostatin inhibitor into the muscle using a non-viral vector (RSET from Invitrogen). Two injections can increase muscle mass in mice up to 60%. This type of muscle growth occurs without training. Dr. Lee feels that this technology could easily be applied to humans (bodybuilders). He feels a small lab or individual could exploit this technology for athletes and bodybuilders for as little as $20,000 to $50,000 (DOLETAS!).

“You can get enormous growth. Any small lab out there, even an individual who knows what they’re doing, could do this. The technology is relatively straightforward.”

http://forum.mesomorphosis.com/steroid-forum/speed-endurance-you-have-134296625.html#ixzz1KBiAKzSL

http://www.mesomorphosis.com/blog/scientists-use-gene-therapy-to-create-perfect-bodybuilder/437/

Ou seja, no fim das contas, não interessa se a tecnologia que envolve a supressão da miostatina vai ajudar Duchenne e outras distrofias musculares, o esquema é vender a tecnologia para o esporte, inclusive fisiculturismo.

Assim, é tudo conflito de interesse…. =[

Anúncios

2 comentários em “Miostatina e crescimento muscular

  1. Pingback: Miostatina e crescimento muscular

  2. Pingback: Suprimindo a Miostatina – Auxílio para o treino de hipertrofia muscular. | Treinamento Esportivo e Desempenho Físico

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