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Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models
Open accessAbstract
A highly conserved signaling pathway involving insulin-like growth factor 1 (IGF1), and a cascade of intracellular components that mediate its effects, plays a major role in the regulation of skeletal muscle growth. A central component in this cascade is the kinase Akt, also called protein kinase B (PKB), which controls both protein synthesis, via the kinases mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK3β), and protein degradation, via the transcription factors of the FoxO family. In this paper, we review the composition and function of this pathway in skeletal muscle fibers, focusing on evidence obtained in vivo by transgenic and knockout models and by muscle transient transfection experiments. Although this pathway is essential for muscle growth during development and regeneration, its role in adult muscle response to mechanical load is less clear. A full understanding of the operation of this pathway could help to design molecularly targeted therapeutics aimed at preventing muscle wasting, which occurs in a variety of pathologic contexts and in the course of aging.
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![Figure 4 Myofiber hypertrophy or atrophy induced by transfection of skeletal muscle with mutants of Akt or FoxO. (A) Regenerating rat soleus muscle transfected with plasmid coding for constitutively active Akt1 linked to a hemagglutinin (HA) epitope. Muscle examined 7 days after transfection; section stained for the HA tag. Note the striking hypertrophy of labeled myofibers compared with untransfected neighbouring fibers. Modified from [69]. (B,C) Adult mouse tibialis anterior muscle transfected by electroporation with plasmid coding for constitutively active Ha-tagged FoxO3. Muscle examined 14 days after transfection; section stained for the HA tag. Note the striking atrophy of labeled myofibers compared with untransfected neighboring fibers. A phase-contrast image of the same field is shown in the right panel. Modified from [91].](/paper-figures/359159bcbb5243a7a8bdb7d6fd83c1df/regulation-of-skeletal-muscle-growth-by-the-igf1-akt-pkb-pathway-insights-from-figure-4.jpg)
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“The Akt‐mTOR pathway is central to the regulation of muscle mass because it promotes protein synthesis and inhibits protein degradation (Schiaffino & Mammucari, 2011).”
From Parkin overexpression protects from ageing‐related loss of muscle mass and strength (2019) · cites this paper as Schiaffino & Mammucari, 2011
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“Additionally, it has been discovered that PEs present in cosmetic preparation protect skin from pigmentation and aging163.”
From The Phytochemical, Biological, and Medicinal Attributes of Phytoecdysteroids: An Updated Review (2021) · cites this paper as [163]
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“These peptides bind the IGF-1 receptor on adjacent fibres, inducing phosphorylation of insulin receptor substrate 1 (IRS-1) and recruitment of PI3K to the membrane, where it converts PIP 2 to PIP 3 (Ji et al., 2025; Rommel et al., 2001; Schiaffino & Mammucari, 2011).”
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“Protein synthesis in muscle is controlled by specific signalling pathways, including phosphatidylinositol-3 kinase (Schiaffino and Mammucari 2011), 5′-AMP-activated protein kinase (Bolster et al. 2002) and mitogen-activated protein kinase (Williamson et al. 2003).”
BackgroundDevelopmental changes of Insulin-like growth factors in the liver and muscle of chick embryos
Liu, Y., Guo, W., Pu, Z., Li, X., Lei, X., Yao, J., & Yang, X. (2016) · Poultry Science · doi:10.3382/ps/pew043 · Cited by 31
“, 1991), and many signaling pathways involving IGF1 were related to muscle growth (Christoffolete et al., 2015; Dupont and Holzenberger, 2003; Schiaffino and Mammucari, 2011).”
BackgroundLi, X., Zhu, Y., Zhang, H., Ma, G., Wu, G., Xiang, A., Shi, X., Yang, G., & Sun, S. (2018) · Genes · doi:10.3390/genes9070333 · Cited by 31
“PI3K (p85α), encoded by PIK3R1 gene, is a key protein involved in the PI3K/AKT signaling pathway [24], which is essential for myogenic differentiation [25,26].”
BackgroundAlterations of signaling pathways in muscle tissues of patients with amyotrophic lateral sclerosis
Yin, F., Ye, F., Tan, L., Liu, K. Y., Xuan, Z., Zhang, J., Wang, W., Zhang, Y., Jiang, X., & Zhang, D. Y. (2012) · Muscle & Nerve · doi:10.1002/mus.23411 · Cited by 30
“Akt has been reported to play a key role in muscle atrophy and hypertrophy.(28) Muscle hypertrophy is correlated with upregulation of Akt, which is activated by insulin-like growth factor-1 (IGF-1).”
BackgroundLunar gravity prevents skeletal muscle atrophy but not myofiber type shift in mice
Hayashi, T., Fujita, R., Okada, R., Hamada, M., Suzuki, R., Fuseya, S., Leckey, J., Kanai, M., Inoue, Y., Sadaki, S., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-04769-3 · Cited by 29
Overload-induced skeletal muscle hypertrophy is not impaired in STZ-diabetic rats
Fortes, M. A. S., Pinheiro, C. H. D. J., Guimarães‐Ferreira, L., Vitzel, K. F., de Vasconcelos, D. A. A., & Curi, R. (2015) · Physiological Reports · doi:10.14814/phy2.12457 · Cited by 29
Wetzel, M. D., & Wenke, J. C. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-018-1753-7 · Cited by 29
Tyganov, S. A., Mochalova, E. P., Belova, S. P., Sharlo, K. A., Rozhkov, S. V., Vilchinskaya, N. A., Paramonova, I. I., Mirzoev, T. M., & Shenkman, B. S. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01252 · Cited by 31
Sahm, A., Hoffmann, S., Koch, P., Henning, Y., Bens, M., Groth, M., Burda, H., Begall, S., Ting, S. C., Goetz, M., et al. (2021) · eLife · doi:10.7554/elife.57843 · Cited by 29
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“Consistent with this, the genetic activation of IGF1 or Akt in skeletal muscle is sufficient to increase muscle mass [11].”
BackgroundMolecular mechanisms of post‐burn muscle wasting and the therapeutic potential of physical exercise
Dombrecht, D., Daele, U. V., Asbroeck, B. V., Schieffelers, D. R., Guns, P., Gebruers, N., Meirte, J., & van Breda, E. (2023) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13188 · Cited by 28
“Two mTORC complexes exist, that is, mTORC1 and mTORC2.(28) The mechanisms of mTORC2 are not fully unravelled, but in vivo research in mice did not reveal a structural impact on skeletal muscle by mTORC2 inhibition.”
BackgroundPaco, S., Kalko, S. G., Jou, C., Rodríguez, M. A., Corbera, J., Francesco Muntoni, A., Feng, L., Rivas, E., Torner, F., Gualandi, F., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077430 · Cited by 29
“Insulin –like growth factor I (IGF-I), whose expression is known to be up-regulated in regenerating muscle in vivo, positively regulates the proliferation and differentiation of satellite cells/ myoblasts in vitro via the Akt/PKB pathway [45] and calcineurin [46].”
BackgroundDang, K., Li, Y.-Z., Gong, L.-C., Xue, W., Wang, H., Goswami, N., & Gao, Y. (2016) · Biology Open · doi:10.1242/bio.015776 · Cited by 29
“It is worth noting that after 14-days, HU atrogin-1 and MuRF1 mRNA expression levels were upregulated, while the phosphorylation level of FoxO1 was significantly increased.”
BackgroundMethodInfluentialShibu, M. A., Hung, T.-H., Chiang, W., & Lin, W. (2018) · Journal of Medicinal Food · doi:10.1089/jmf.2017.3941 · Cited by 29
“4 Natural products such as acidic polysaccharide and hydroxypropyl methyl cellulose can suppress HFD-induced disease risk.”
Muscle wasting: An overview of recent developments in basic research
Palus, S., von Haehling, S., & Springer, J. (2014) · International Journal of Cardiology · doi:10.1016/j.ijcard.2014.08.086 · Cited by 29
Yoshimoto, Y., & Oishi, Y. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108357 · Cited by 28
Ranasinghe, T., Seo, Y., Park, H., Choe, S., & Cha, S. (2024) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2024.136215 · Cited by 27
Margolis, L. M., Berryman, C. E., Murphy, N. E., Carrigan, C. T., Young, A., Carbone, J. W., & Pasiakos, S. M. (2018) · Physiological Reports · doi:10.14814/phy2.13931 · Cited by 26
“When miR-19b-3p, miR-222-3p, miR-324-3p, and miR-486-5p expression is higher in the muscle, there is lower PTEN expression, increased activity of p-AKTThr473, and lower activity of p-FOXO1Thr24 and MURF1 expression.”
BackgroundInfluentialDiet and redox state in maintaining skeletal muscle health and performance at high altitude
Rathor, R., Suryakumar, G., & Singh, S. N. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.07.024 · Cited by 28
Role of MicroRNAs and Long Non-Coding RNAs in Sarcopenia
Lee, J., & Kang, H. (2022) · Cells · doi:10.3390/cells11020187 · Cited by 28
“The IGF-1 signaling pathway plays an important role in skeletal muscle growth, differentiation, and regeneration [46,47].”
BackgroundGiannos, P., Prokopidis, K., Raleigh, S. M., Kelaiditi, E., & Hill, M. W. (2022) · Scientific Reports · doi:10.1038/s41598-022-15578-9 · Cited by 28
Fernández, T., Briceño, F. A. C., Espinosa‐Ramírez, M., García-Valdés, P., López‐Fuenzalida, A., Riquelme, A. J., Arab, J. P., Cabrera, D., Arrese, M. A., & Francisco Barrera, M. (2020) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2020.1810563 · Cited by 28
“and important pathways of protein catabolism such as MuRF1 and atrogin-1 [64].”
BackgroundLi, Z., Abdalla, B. A., Zheng, M., He, X., Cai, B., Han, P., Ouyang, H., Chen, B., Nie, Q., & Zhang, X. (2017) · Molecular Genetics and Genomics · doi:10.1007/s00438-017-1364-7 · Cited by 27
“The kinase Akt/protein kinase B (PKB) targets mTOR and glycogen synthase kinase 3β, thus regulating protein degradation, and also targets a FOXO family transcription factor, thus regulating protein synthesis (Schiaffino and Mammucari 2011).”
BackgroundLambert, B. S., Shimkus, K. L., Fluckey, J. D., Riechman, S. E., Greene, N. P., Cardin, J. M., & Crouse, S. F. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00689.2013 · Cited by 28
de la serrana, D. G., Fuentes, E. N., Martín, S., Johnston, I. A., & Macqueen, D. J. (2017) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2017.01.017 · Cited by 27
“The hormones Igf-I and Igf-II act as endocrine factors (Laron, 58 1996; Wood et al. 2005), but are also released locally by tissues, including skeletal muscle 59 (Schiaffino and Mammucari, 2011).”
Extracellular matrix in skeletal muscle injury and atrophy: mechanisms and therapeutic implications
Ge, X., Jin, Y., He, J., Jia, Z., Liu, Y., & Xu, Y. X. (2025) · Journal of Orthopaedic Translation · doi:10.1016/j.jot.2025.03.004 · Cited by 33
“Numerous signaling cascades are instrumental in the modulation of muscle wasting, such as the insulin/IGF-1-Protein Kinase B (AKT)-mammalian Target of Rapamycin (mTOR) axis, which facilitates protein anabolism and suppresses proteolysis [25].”
Time course of diaphragm function recovery after controlled mechanical ventilation in rats
Thomas, D., Maes, K., Agten, A., Heunks, L. M. A., Dekhuijzen, R. P. N., Decramer, M., van Hees, H. W. H., & Gayan‐Ramirez, G. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00302.2012 · Cited by 26
Interspecies Organogenesis for Human Transplantation
Crane, A. T., Aravalli, R. N., Asakura, A., Grande, A. W., Krishna, V. D., Carlson, D. F., Cheeran, M. C. ‐., Danczyk, G., Dutton, J. R., Hackett, P. B., et al. (2019) · Cell Transplantation · doi:10.1177/0963689719845351 · Cited by 26
Skeletal muscle IGF-1 is lower at rest and after resistance exercise in humans with obesity
Sullivan, B. P., Weiss, J. A., Nie, Y., Garner, R. T., Drohan, C. J., Kuang, S., Stout, J., & Gavin, T. P. (2020) · European Journal of Applied Physiology · doi:10.1007/s00421-020-04509-z · Cited by 26
Tyganov, S. A., Mochalova, E. P., Belova, S. P., Sharlo, K. A., Rozhkov, S. V., Kalashnikov, V. E., Turtikova, O. V., Mirzoev, T. M., & Shenkman, B. S. (2021) · Scientific Reports · doi:10.1038/s41598-021-89362-6 · Cited by 26
Graça, F. A., Sheffield, N., Puppa, M., Finkelstein, D., Hunt, L. C., & Demontis, F. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009926 · Cited by 27
“Altogether, these findings indicate that Gsk3, similar to Deaf1, regulates muscle mass in Drosophila (Fig 3), as observed in mammals [14,41,56].”
BackgroundMethodXu, J., Strasburg, G. M., Reed, K. M., & Velleman, S. G. (2022) · PLoS ONE · doi:10.1371/journal.pone.0262576 · Cited by 28
“As an upstream signal, IGF-1 can interact with IGF-1 receptor, activating mTOR/S6K signal transduction via PI3K/Akt pathway [38, 49, 91].”
BackgroundChycki, J., Czuba, M., Gołaś, A., Zając, A., Fidos-Czuba, O., Młynarz, A., & Smółka, W. (2016) · Journal of Human Kinetics · doi:10.1515/hukin-2016-0013 · Cited by 26
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“The insulin/IGF-1- Akt pathway increases skeletal muscle protein synthesis via inhibiting glycogen synthase kinase 3β and activating the mechanistic target of rapamycin complex 1 (mTORC1) signaling [9].”
BackgroundAncel, S., Michaud, J., Migliavacca, E., Jomard, C., Fessard, A., Garcia, P., Karaz, S., Raja, S., Jacot, G. E., Desgeorges, T., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci163648 · Cited by 25
“The AKT serine/threonine kinase controls myogenic differentiation and is a central regulator of anabolic processes and muscle protein synthesis (44), which were regulated in hMPs in response to PN (Figure 1G).”
Li, Y., Zhang, F., Modrak, S., Little, A., & Zhang, H. (2019) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.14221 · Cited by 25
“Activation of IGFR-1 by IGF-1 recruits and activates insulin receptor substrate (IRS), which in turn recruits and activates phosphatidylinositol-3 kinase (PI3K) to generate phosphoinositide-3,4,5-triphosphate (PIP3).”
BackgroundInfluentialEffect of GLP-1 receptor agonist, liraglutide, on muscle in spontaneously diabetic torii fatty rats
Yamada, S., Ogura, Y., Inoue, K., Tanabe, J., Sugaya, T., Ohata, K., Nagai, Y., Natsuki, Y., Hoshino, S., Watanabe, S., et al. (2022) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111472 · Cited by 25
Wang, S., Tan, B., Xiao, L., Zhao, X., Zeng, J., Hong, L., Yang, J., Cai, G., Zheng, E., Wu, Z., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094600 · Cited by 25
McIntosh, M. C., Sexton, C. L., Godwin, J. S., Ruple, B. A., Michel, J. M., Plotkin, D. L., Ziegenfuss, T. N., Lopez, H. L., Smith, R. C., Dwaraka, V. B., et al. (2023) · Cells · doi:10.3390/cells12060898 · Cited by 28
Hayakawa, N., Fukumura, J., Yasuno, H., Fujimoto-Ouchi, K., & Kitamura, H. (2015) · Biomedical Research · doi:10.2220/biomedres.36.71 · Cited by 25
“IGF-1 promotes phosphorylation of AKT and the activated AKT downregulates MAFbx and MuRF1 via downstream FOXO inhibition (39).”
Background
Metadata
- Authors
- Schiaffino, S., & Mammucari, C.
- Affiliations
- Veneto Institute of Molecular Medicine (IT)
- University of Padua (IT)
- Corresponding author
- Schiaffino, Stefano
- Venue
- Skeletal Muscle
- Published
- 2011
- Volume
- 1
- Issue
- 1
- Pages
- 4
- ISSN
- 2044-5040 (ISSN-L)
- PMC
- PMC3143906
- OpenAlex
- W2150059080
- Cited by
- 816
- References
- 150
- Citations by year
- 2026: 42 · 2025: 70 · 2024: 68 · 2023: 63 · 2022: 55 · 2021: 59 · 2020: 56 · 2019: 69 · 2018: 68 · 2017: 57 · 2016: 42 · 2015: 46 · 2014: 48 · 2013: 44 · 2012: 23
- FWCI
- 15.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Skeletal Muscle (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- European Commission
- Università degli Studi di Padova
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- skeletal muscle growth, IGF-1 signaling, mTOR, GSK3β, FOXO transcription factors, muscle regeneration, myogenesis, mechanical loading, muscle atrophy, muscle protein synthesis, protein degradation
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