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PMID:19357233

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Citation

Trendelenburg, AU, Meyer, A, Rohner, D, Boyle, J, Hatakeyama, S and Glass, DJ (2009) Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am. J. Physiol., Cell Physiol. 296:C1258-70

Abstract

Myostatin is a negative regulator of skeletal muscle size, previously shown to inhibit muscle cell differentiation. Myostatin requires both Smad2 and Smad3 downstream of the activin receptor II (ActRII)/activin receptor-like kinase (ALK) receptor complex. Other transforming growth factor-beta (TGF-beta)-like molecules can also block differentiation, including TGF-beta(1), growth differentiation factor 11 (GDF-11), activins, bone morphogenetic protein 2 (BMP-2) and BMP-7. Myostatin inhibits activation of the Akt/mammalian target of rapamycin (mTOR)/p70S6 protein synthesis pathway, which mediates both differentiation in myoblasts and hypertrophy in myotubes. Blockade of the Akt/mTOR pathway, using small interfering RNA to regulatory-associated protein of mTOR (RAPTOR), a component of TOR signaling complex 1 (TORC1), increases myostatin-induced phosphorylation of Smad2, establishing a myostatin signaling-amplification role for blockade of Akt. Blockade of RAPTOR also facilitates myostatin's inhibition of muscle differentiation. Inhibition of TORC2, via rapamycin-insensitive companion of mTOR (RICTOR), is sufficient to inhibit differentiation on its own. Furthermore, myostatin decreases the diameter of postdifferentiated myotubes. However, rather than causing upregulation of the E3 ubiquitin ligases muscle RING-finger 1 (MuRF1) and muscle atrophy F-box (MAFbx), previously shown to mediate skeletal muscle atrophy, myostatin decreases expression of these atrophy markers in differentiated myotubes, as well as other genes normally upregulated during differentiation. These findings demonstrate that myostatin signaling acts by blocking genes induced during differentiation, even in a myotube, as opposed to activating the distinct "atrophy program." In vivo, inhibition of myostatin increases muscle creatine kinase activity, coincident with an increase in muscle size, demonstrating that this in vitro differentiation measure is also upregulated in vivo.

Links

PubMed Online version:10.1152/ajpcell.00105.2009

Keywords

Activin Receptors, Type I/antagonists & inhibitors; Activin Receptors, Type I/metabolism; Adaptor Proteins, Signal Transducing; Animals; Benzamides/pharmacology; Carrier Proteins/metabolism; Cell Differentiation/drug effects; Cell Size/drug effects; Cells, Cultured; Creatine Kinase/metabolism; Dioxoles/pharmacology; Follistatin/pharmacology; Humans; Insulin-Like Growth Factor I/metabolism; Mice; Mice, SCID; Muscle Fibers, Skeletal/drug effects; Muscle Fibers, Skeletal/enzymology; Muscle Fibers, Skeletal/pathology; Muscle Proteins/metabolism; Myoblasts, Skeletal/drug effects; Myoblasts, Skeletal/enzymology; Myoblasts, Skeletal/pathology; Myostatin/antagonists & inhibitors; Myostatin/metabolism; Organ Size; Phosphorylation; Protein Kinase Inhibitors/pharmacology; Protein Kinases/genetics; Protein Kinases/metabolism; Proteins/metabolism; Proto-Oncogene Proteins c-akt/metabolism; RNA Interference; RNA, Small Interfering/metabolism; Ribosomal Protein S6 Kinases, 70-kDa/metabolism; SKP Cullin F-Box Protein Ligases/metabolism; Signal Transduction; Smad2 Protein/genetics; Smad2 Protein/metabolism; Smad3 Protein/genetics; Smad3 Protein/metabolism; TOR Serine-Threonine Kinases; Transfection; Ubiquitin-Protein Ligases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:GDF8

involved_in

GO:0033673: negative regulation of kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:GDF8

GO:0033673: negative regulation of kinase activity

ECO:0000315:

P

Results section/ Increased muscle weight and CK activity... Section; Fig. 7 B; Show Creatine Kinase activity increased by myostatin expression inhitbion in vivo [mice], activity bio marker used. Mice had Severe Combined Immunodeficiency and no MSTN mutations

complete
CACAO 6339

HUMAN:GDF8

involved_in

GO:0046716: muscle cell cellular homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GDF8

involved_in

GO:0051898: negative regulation of protein kinase B signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GDF8

involved_in

GO:0045662: negative regulation of myoblast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GDF8

GO:0045662: negative regulation of myoblast differentiation

ECO:0000314:

P

Fig. 1 & 4A

complete
CACAO 6336

HUMAN:GDF8

GO:0046716: muscle cell homeostasis

ECO:0000314:

P

Results section/ Myostatin reduces diameters...section/last sentence; Fig. 5c; states myostatin inhibits genes required for muscle maintenance [homeostatsis of muscle] instead of alternative atrophy pathway

complete
CACAO 6337

HUMAN:GDF8

GO:0051898: negative regulation of protein kinase B signaling cascade

ECO:0000314:

P

Fig. 3; Fig 4; demonstrate that mysostatin inhibits the activation of the Akt signaling pathway in differentiating HuSkMC

complete
CACAO 6521

HUMAN:TGFB1

involved_in

GO:0045596: negative regulation of cell differentiation

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TGFB1

GO:0045596: negative regulation of cell differentiation

ECO:0000270:

P

Fig. 1. shows inhibition by myostatin of human skeletal muscle cells (HuSkMC).

complete
CACAO 2295


See also

References

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