Regulation of muscle growth by multiple ligands signaling through activin type II receptors
Se-Jin Lee,Lori A. Reed,Monique V. Davies,Stefan Girgenrath,Mary E.P. Goad,Kathy Tomkinson,Jill F. Wright,Christopher M. Barker,Gregory Ehrmantraut,James Holmstrom,Betty Trowell,Barry Gertz,Man Shiow Jiang,Suzanne Sebald,Martin M. Matzuk,En Li,En Li,Li Fang Liang,Edwin Quattlebaum,Ronald L. Stotish,Neil M. Wolfman +20 more
TLDR
A potent myostatin inhibitor, a soluble form of the activin type IIB receptor (ACVR2B), is described, which can cause dramatic increases in muscle mass when injected into wild-type mice.Abstract:
Myostatin is a secreted protein that normally functions as a negative regulator of muscle growth. Agents capable of blocking the myostatin signaling pathway could have important applications for treating human muscle degenerative diseases as well as for enhancing livestock production. Here we describe a potent myostatin inhibitor, a soluble form of the activin type IIB receptor (ACVR2B), which can cause dramatic increases in muscle mass (up to 60% in 2 weeks) when injected into wild-type mice. Furthermore, we show that the effect of the soluble receptor is attenuated but not eliminated in Mstn-/- mice, suggesting that at least one other ligand in addition to myostatin normally functions to limit muscle growth. Finally, we provide genetic evidence that these ligands signal through both activin type II receptors, ACVR2 and ACVR2B, to regulate muscle growth in vivo.read more
Citations
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Cancer cachexia: mediators, signaling, and metabolic pathways.
TL;DR: Progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies.
Journal ArticleDOI
Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival
Xiaolan Zhou,Jin Lin Wang,John Lu,Yanping Song,Keith S. Kwak,Qingsheng Jiao,Robert Rosenfeld,Qing Chen,Thomas Boone,W. Scott Simonet,David L. Lacey,Alfred L. Goldberg,Hq Han +12 more
TL;DR: It is shown that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy, establishing a crucial link between activation of the ActR IIB pathway and the development of cancer Cachexia.
Journal ArticleDOI
Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy
Francesco S. Loffredo,Matthew L. Steinhauser,Steven M. Jay,Joseph Gannon,James R. Pancoast,Pratyusha Yalamanchi,Manisha Sinha,Manisha Sinha,Claudia Dall'Osso,Claudia Dall'Osso,Danika Mei Po Khong,Danika Mei Po Khong,J Shadrach,J Shadrach,Christine M. Miller,Christine M. Miller,Britta Singer,Alex Stewart,Nikolaos Psychogios,Robert E. Gerszten,Adam J. Hartigan,Adam J. Hartigan,Mi-Jeong Kim,Mi-Jeong Kim,Thomas Serwold,Thomas Serwold,Amy J. Wagers,Amy J. Wagers,Amy J. Wagers,Richard T. Lee +29 more
TL;DR: Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.
Journal ArticleDOI
Signaling in muscle atrophy and hypertrophy.
TL;DR: Understanding the signaling that regulates muscle mass may provide potential therapeutic targets for the prevention and treatment of muscle wasting in metabolic and neuromuscular diseases.
Journal ArticleDOI
Muscle wasting in disease: molecular mechanisms and promising therapies
TL;DR: Major advances in the understanding of the cellular mechanisms that regulate the protein balance in muscle include the identification of several cytokines, particularly myostatin, and a common transcriptional programme that promotes muscle wasting.
References
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Journal ArticleDOI
Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.
TL;DR: Results suggest that GDF-8 functions specifically as a negative regulator of skeletal muscle growth, which is significantly larger than wild-type animals and show a large and widespread increase in skeletal muscle mass.
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Double muscling in cattle due to mutations in the myostatin gene
TL;DR: The similarity in phenotypes of double-muscled cattle and myostatin null mice suggests that mystatin performs the same biological function in these two species and is a potentially useful target for genetic manipulation in other farm animals.
Journal ArticleDOI
Regulation of myostatin activity and muscle growth
TL;DR: The findings suggest that the propeptide, follistatin, or other molecules that block signaling through this pathway may be useful agents for enhancing muscle growth for both human therapeutic and agricultural applications.
Journal ArticleDOI
A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle.
Luc Grobet,Luis José Royo Martin,Dominique Poncelet,Dimitri Pirottin,Benoît Brouwers,Juliette Riquet,Andreina Schoeberlein,S. Dunner,François Ménissier,Julio Massabanda,Ruedi Fries,R. Hanset,Michel Georges +12 more
TL;DR: It is demonstrated that a mutation in bovine MSTN, which encodes myostatin, a member of the TGFβ superfamily, is responsible for the double-muscled phenotype, and an 11-bp deletion in the coding sequence for the bioactive carboxy-termihal domain of the protein causing the muscular hypertrophy observed in Belgian Blue cattle is reported.
Journal ArticleDOI
Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child
Markus Schuelke,Kathryn R. Wagner,Leslie E Stolz,Christoph Hübner,Thomas Riebel,Wolfgang Kömen,Thomas Braun,James F. Tobin,Se-Jin Lee +8 more
TL;DR: A mutation in the gene for myostatin is described in a child with muscle hypertrophy and unusual strength and greater understanding of muscle growth and maintenance is important for future therapies.