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Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size
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.
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“Accordingly, inhibition of SMAD 2 and SMAD 3 is sufficient to induce muscle growth [4, 5].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [5]
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“Myostatin is a powerful inhibitor of muscle mass growth and development that acts via Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and reducing myotube size [111].”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [111]
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Metadata
- Authors
- Trendelenburg, A. U., Meyer, A., Rohner, D., Boyle, J., Hatakeyama, S., & Glass, D. J.
- Affiliations
- Novartis (Switzerland) (CH)
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2009-06
- Volume
- 296
- Issue
- 6
- Pages
- C1258-C1270
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- OpenAlex
- W2033924360
- Cited by
- 792
- References
- 54
- Citations by year
- 2026: 31 · 2025: 38 · 2024: 28 · 2023: 43 · 2022: 38 · 2021: 65 · 2020: 61 · 2019: 48 · 2018: 49 · 2017: 47 · 2016: 39 · 2015: 46 · 2014: 55 · 2013: 69 · 2012: 52
- FWCI
- 18.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
- Keywords
- myostatin, myogenesis, Akt/mTOR signaling, TORC1, TORC2, p70S6K, raptors, Rictor, Smad2, Smad3, activin receptors, muscle hypertrophy, muscle atrophy, MuRF1, atrogin-1, creatine kinase, skeletal muscle size
- MeSH terms
- Tripartite Motif Proteins, Regulatory-Associated Protein of mTOR, Rapamycin-Insensitive Companion of mTOR Protein, Animals, Benzamides, Carrier Proteins, Cell Differentiation, Cells, Cultured, Creatine Kinase, Dioxoles, Humans, Insulin-Like Growth Factor I, Muscle Proteins, Organ Size, Phosphorylation, Protein Kinases, Proteins, Transfection, Signal Transduction, Mice, SCID, Muscle Fibers, Skeletal, Activin Receptors, Type I, Myoblasts, Skeletal, RNA Interference, RNA, Small Interfering, Follistatin, Ribosomal Protein S6 Kinases, 70-kDa, Ubiquitin-Protein Ligases, SKP Cullin F-Box Protein Ligases, Protein Kinase Inhibitors, Cell Size, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, Mice, Smad2 Protein, Smad3 Protein, Myostatin, TOR Serine-Threonine Kinases
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