Myostatin, a Negative Regulator of Muscle Growth, Functions by Inhibiting Myoblast Proliferation

Thomas, Mark; Langley, Brett; Berry, Carole; Sharma, Mridula; Kirk, S P; Bass, J. J.; Kambadur, Ravi

doi:10.1074/jbc.m004356200

Cited by 882 publications

(760 citation statements)

References 34 publications

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“…Myostatin enters the bloodstream as a latent precursor protein and then undergoes a proteolytic process to become a mature peptide (free from the propeptide) that binds to extracellular activin type II receptor (ActRIIB) (Kostek et al 2009). Binding of myostatin to ActRIIB induces intracellular activation of Smad proteins; through this pathway, myostatin modulates myoblast proliferation (Thomas et al 2000) and differentiation (Ríos et al 2002), and thus ultimately muscle mass. The Lys(K)153Arg(R) amino acid replacement is found within the active mature peptide of the myostatin protein and could theoretically influence (1) proteolytic processing with its propeptide or (2) affinity to bind with ActRIIB (Lee and McPherron 2001;Jiang et al 2004).…”

Section: Resultsmentioning

confidence: 99%

The K153R variant in the myostatin gene and sarcopenia at the end of the human lifespan

González-Freire

Rodríguez-Romo

Santiago

et al. 2010

AGE

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We studied the A55T, E164K, I225T, K153R and P198A variants in the myostatin (GDF8) gene, muscle strength and mass, and physical function during daily living in 41 nonagenarians [33 women, age range, 90, 97]. No participant carried a mutant allele of the aforementioned variants, except three participants (all women), who carried the R allele of the K153R polymorphism, with one of them (woman aged 96 years) being homozygous. Overall, in KR women muscle phenotype values (1RM leg press and estimated muscle mass) were low-to-normal compared to the whole group (∼25th-50th percentile), and their functional capacity (Barthel and Tinetti tests) was normal. In the woman bearing the RR genotype, values of muscle mass and functional capacity were below the 25th percentile. She is the first RR Caucasian whose phenotype has been characterised specifically. In summary, heterozygosity for the GDF8 K153R polymorphism does not seem to exert a negative influence on the muscle phenotypes of women who are at the end of the human lifespan, yet homozygosity might do so. More research on larger cohorts of nonagenarians is needed to corroborate the present findings.

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Section: Resultsmentioning

confidence: 99%

The K153R variant in the myostatin gene and sarcopenia at the end of the human lifespan

González-Freire

Rodríguez-Romo

Santiago

et al. 2010

AGE

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“…The Lys(K)153Arg (R) amino acid replacement is found within the active mature peptide of the myostatin protein; it could theoretically influence proteolytic processing with its propeptide, or affinity to bind with the extracellular activin-type II receptor B. The latter results in intracellular activation of the SMAD pathway, through which myostatin induces myoblast proliferation (Thomas et al 2000) and differentiation (Rios et al 2002), and thus muscle mass growth (Kostek et al 2009). The frequency of the mutant R allele is~3-4% among Caucasians, with a frequency of mutant homozygotes (RR) below 1% (Corsi et al 2002;Ferrell et al 1999;Kostek et al 2009).…”

Section: Genotype-phenotype Association Studiesmentioning

confidence: 99%

Genes and the ageing muscle: a review on genetic association studies

Garatachea

Lucía

2011

AGE

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Western populations are living longer. Ageing decline in muscle mass and strength (i.e. sarcopenia) is becoming a growing public health problem, as it contributes to the decreased capacity for independent living. It is thus important to determine those genetic factors that interact with ageing and thus modulate functional capacity and skeletal muscle phenotypes in older people. It would be also clinically relevant to identify 'unfavourable' genotypes associated with accelerated sarcopenia. In this review, we summarized published information on the potential associations between some genetic polymorphisms and muscle phenotypes in older people. A special emphasis was placed on those candidate polymorphisms that have been more extensively studied, i.e. angiotensinconverting enzyme (ACE) gene I/D, α-actinin-3 (ACTN3) R577X, and myostatin (MSTN) K153R, among others. Although previous heritability studies have indicated that there is an important genetic contribution to individual variability in muscle phenotypes among old people, published data on specific gene variants are controversial. The ACTN3 R577X polymorphism could influence muscle function in old women, yet there is controversy with regards to which allele (R or X) might play a 'favourable' role. Though more research is needed, up-to-date MSTN genotype is possibly the strongest candidate to explain variance among muscle phenotypes in the elderly. Future studies should take into account the association between muscle phenotypes in this population and complex gene-gene and gene-environment interactions.

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“…The porcine Mst gene has been molecularly cloned and characterised, but a mutation that confers the enlarged muscle phenotype has not been described (Ji et al, 1998). Mst arrests muscle cells in the G 1 and G 2 phases of the cell cycle, through the up-regulation of cyclin-dependent kinase (cdk) inhibitor p21 and down-regulation of cdk-2, thereby inhibiting cell proliferation (Thomas et al, 2000). This inhibition is mediated, at least in part, through the p38 MAPK stress response pathway (Philip et al, 2005) (Figure 4).…”

Section: Fibre Number: Mediators Of Muscle Hyperplasiamentioning

confidence: 99%

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

Chang

2007

Animal

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The molecular basis and control of the biochemical and biophysical properties of skeletal muscle, regarded as muscle phenotype, are examined in terms of fibre number, fibre size and fibre types. A host of external factors or stimuli, such as ligand binding and contractile activity, are transduced in muscle into signalling pathways that lead to protein modifications and changes in gene expression which ultimately result in the establishment of the specified phenotype. In skeletal muscle, the key signalling cascades include the Ras-extracellular signal regulated kinase-mitogen activated protein kinase (Erk-MAPK), the phosphatidylinositol 3 0 -kinase (PI3K)-Akt1, p38 MAPK, and calcineurin pathways. The molecular effects of external factors on these pathways revealed complex interactions and functional overlap. A major challenge in the manipulation of muscle of farm animals lies in the identification of regulatory and target genes that could effect defined and desirable changes in muscle quality and quantity. To this end, recent advances in functional genomics that involve the use of micro-array technology and proteomics are increasingly breaking new ground in furthering our understanding of the molecular determinants of muscle phenotype.

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Myostatin, a Negative Regulator of Muscle Growth, Functions by Inhibiting Myoblast Proliferation

Cited by 882 publications

References 34 publications

The K153R variant in the myostatin gene and sarcopenia at the end of the human lifespan

The K153R variant in the myostatin gene and sarcopenia at the end of the human lifespan

Genes and the ageing muscle: a review on genetic association studies

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

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