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Tytuł:
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Activin A more prominently regulates muscle mass in primates than does GDF8.
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Autorzy:
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Latres E; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Mastaitis J; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Fury W; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Miloscio L; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Trejos J; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Pangilinan J; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Okamoto H; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Cavino K; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Na E; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Papatheodorou A; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Willer T; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Bai Y; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Hae Kim J; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Rafique A; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Jaspers S; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Stitt T; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Murphy AJ; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Yancopoulos GD; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Gromada J; Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
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Źródło:
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Nature communications [Nat Commun] 2017 Apr 28; Vol. 8, pp. 15153. Date of Electronic Publication: 2017 Apr 28.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Original Publication: [London] : Nature Pub. Group
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MeSH Terms:
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Activins/*metabolism
Hypertrophy/*pathology
Muscle Hypotonia/*pathology
Muscle, Skeletal/*growth & development
Myostatin/*metabolism
Activin Receptors, Type II/metabolism ; Activins/antagonists & inhibitors ; Animals ; Antibodies, Monoclonal/pharmacology ; Body Mass Index ; Dexamethasone/pharmacology ; Humans ; Isometric Contraction/physiology ; Macaca fascicularis ; Male ; Mice ; Mice, Inbred C57BL ; Mice, SCID ; Muscle, Skeletal/physiology ; Myostatin/antagonists & inhibitors ; Rats
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References:
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Substance Nomenclature:
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0 (Antibodies, Monoclonal)
0 (Myostatin)
0 (activin A)
104625-48-1 (Activins)
7S5I7G3JQL (Dexamethasone)
EC 2.7.11.30 (Activin Receptors, Type II)
EC 2.7.11.30 (activin receptor type II-B)
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Entry Date(s):
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Date Created: 20170429 Date Completed: 20181119 Latest Revision: 20181119
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Update Code:
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20240105
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PubMed Central ID:
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PMC5414365
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DOI:
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10.1038/ncomms15153
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PMID:
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28452368
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Growth and differentiation factor 8 (GDF8) is a TGF-β superfamily member, and negative regulator of skeletal muscle mass. GDF8 inhibition results in prominent muscle growth in mice, but less impressive hypertrophy in primates, including man. Broad TGF-β inhibition suggests another family member negatively regulates muscle mass, and its blockade enhances muscle growth seen with GDF8-specific inhibition. Here we show that activin A is the long-sought second negative muscle regulator. Activin A specific inhibition, on top of GDF8 inhibition, leads to pronounced muscle hypertrophy and force production in mice and monkeys. Inhibition of these two ligands mimics the hypertrophy seen with broad TGF-β blockers, while avoiding the adverse effects due to inhibition of multiple family members. Altogether, we identify activin A as a second negative regulator of muscle mass, and suggest that inhibition of both ligands provides a preferred therapeutic approach, which maximizes the benefit:risk ratio for muscle diseases in man.