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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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“Following IGF-1 receptor binding, a cascade of intracellular signalling is initiated that represents a crossroads in protein metabolism, stimulating protein synthesis via downstream targets, such as Protein Kinase B and mammalian target of rapamycin, while suppressing degradation through phosphorylation of Forkhead bo…”
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“In CIC, upregulation of dsRNA-dependent protein kinase (PKR) leads to phosphorylation of eIF2, which prevents its conversion to the active GTP-bound form, thereby repressing muscle protein synthesis [42,43].”
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“In addition, previous research demonstrated that GH/IGF-1 signaling is crucial for regulating the skeletal muscle growth (Schiaffino and Mammucari, 2011).”
BackgroundIGF1 promotes human myotube differentiation toward a mature metabolic and contractile phenotype
Dreher, S. I., Grubba, P., von Toerne, C., Moruzzi, A., Maurer, J. A., Goj, T., Birkenfeld, A. L., Peter, A., Loskill, P., Hauck, S. M., et al. (2024) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00654.2023 · Cited by 20
Depletion of insulin receptors leads to β-cell hyperplasia in zebrafish
Yang, B., Zhai, G., Gong, Y., Su, J., Han, D. H., Yin, Z., & Xie, S. (2017) · 中国科学通报：英文版 · doi:10.1016/j.scib.2017.03.001 · Cited by 18
He, L., Roie, E. V., Bogaerts, A., Morse, C. I., Delecluse, C., Verschueren, S., & Thomis, M. A. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2018.06.030 · Cited by 20
“AKT, also known as protein kinase B (PKB), is a critical regulator of muscle growth through the IGF1-AKT/ PKB pathway (Schiaffino and Mammucari, 2011).”
BackgroundHu, L., Han, F., Chen, L., Peng, X., Chen, D.-W., Wu, D., Che, L., & Zhang, K.-Y. (2018) · Genes & Nutrition · doi:10.1186/s12263-018-0612-8 · Cited by 18
Natural constituents from food sources: potential therapeutic agents against muscle wasting
Shen, S., Yu, H., Gan, L., Yang, Y., & Lin, L. (2019) · Food & Function · doi:10.1039/c9fo00912d · Cited by 20
Hernandez, S. J., Fote, G., Reyes-Ortiz, A. M., Steffan, J. S., & Thompson, L. M. (2021) · Matrix Biology Plus · doi:10.1016/j.mbplus.2021.100089 · Cited by 17
Angelica Sinensis promotes myotube hypertrophy through the PI3K/Akt/mTOR pathway
Yeh, T., Hsu, C.-C., Yang, S., Hsu, M., & Liu, J. (2014) · BMC Complementary and Alternative Medicine · doi:10.1186/1472-6882-14-144 · Cited by 19
“The phosphatidylinositol 3-kinase (PI3K)/ Akt (also termed PKB)/mammalian target of rapamycin (mTOR) pathway is recognized as a possible mechanism that regulates muscle mass [4-6].”
BackgroundSignaling networks governing skeletal muscle growth, atrophy, and cachexia
Joshi, A. S., da Silva, M. T., Kumar, S., & Kumar, A. (2025) · Skeletal Muscle · doi:10.1186/s13395-025-00397-z · Cited by 25
“Since TSC2 suppresses the activity of the Rheb, a selective activator of mTORC1, inhibition of TSC2 by Akt results in activation of mTORC1 [36].”
InfluentialGonzález-Luis, A., Llinares-Arvelo, V., Martínez‐Alberto, C. E., Hernández-Carballo, C., Fernández, C. M., Navarro‐González, J. F., & Donate‐Correa, J. (2025) · European Journal of Endocrinology · doi:10.1093/ejendo/lvaf223 · Cited by 20
Effects of insulin like growth factors on early embryonic chick limb myogenesis
Mohammed, R. H., Anderton, H., Brameld, J. M., & Sweetman, D. (2017) · PLoS ONE · doi:10.1371/journal.pone.0185775 · Cited by 17
Yan, X.-M., Zhang, Z., Liu, J., Li, N., Yang, G.-W., Luo, D., Zhang, Y., Yuan, B., Jiang, H., & Zhang, J. (2020) · Animal Bioscience · doi:10.5713/ajas.20.0317 · Cited by 16
“The core element of this cascade is the kinase Akt, which is also known as protein kinase B (PKB) and controls protein syn thesis through the kinases mTOR and GSK3b and regulates the degradation of FoxO family transcription factors [27].”
dos Santos, M. R., & Storer, T. W. (2022) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2021.11.012 · Cited by 17
Scaling of nuclear numbers and their spatial arrangement in skeletal muscle cell size regulation
Hansson, K., & Eftestøl, E. (2023) · Molecular Biology of the Cell · doi:10.1091/mbc.e22-09-0424 · Cited by 17
“, 2009), and thus influences Dp, while Sp and Dp are regulated by the extracellular cues mediated by the IGF-1 that leads to intracellular activation of the Akt/mTOR pathway that causes a net protein accumulation by promoting protein synthesis and inhibiting proteolysis (Schiaffino and Mammucari, 2011).”
BackgroundAshwagandha Ethanol Extract Attenuates Sarcopenia-Related Muscle Atrophy in Aged Mice
Ko, J.-S., Chang, B., Choi, Y., Choi, J., Kwon, H., Lee, J., Kim, S.-Y., & Choung, S. (2024) · Nutrients · doi:10.3390/nu16010157 · Cited by 19
“Numerous studies have demonstrated that heightened PI3K and AKT activity directly or indirectly promotes the induction of downstream myogenic proteins, such as Myogenin and MyoD, thereby expediting the differentiation and fusion of muscle cells [31,41,42].”
Ahmad, S. S., Ahmad, K., Lim, J. H., Shaikh, S., Lee, E. J., & Choi, I. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.131411 · Cited by 17
Virus integration and genome influence in approaches to stem cell based therapy for andro-urology
Li, L., Zhang, D., Li, P., Damaser, M. S., & Zhang, Y. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.10.012 · Cited by 17
Skeletal muscle Ca2+ mishandling: Another effect of bone-to-muscle signaling
Regan, J. N., Waning, D. L., & Guise, T. A. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.11.007 · Cited by 16
Bareja, A., Hodgkinson, C. P., Soderblom, E. J., Waitt, G. M., & Dzau, V. J. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002406 · Cited by 17
Developmental Programming and Postnatal Modulations of Muscle Development in Ruminants
Gundersen, K., & Anas, M. (2025) · Biology · doi:10.3390/biology14080929 · Cited by 19
“The IGF-1/mTOR signaling pathway is a key driver of muscle protein synthesis, responding to anabolic stimuli, such as growth hormones (GHs) and nutrient availability [21,22].”
Inferring the in vivo cellular program of developing bovine skeletal muscle from expression data
Hudson, N. J., Lyons, R. E., Reverter, A., Greenwood, P. L., & Dalrymple, B. P. (2013) · Gene Expression Patterns · doi:10.1016/j.gep.2013.02.001 · Cited by 18
“Insulin-like growth factors and receptors We observed very little change in the expression of IGF1 (a key driver of muscle growth) (Schiaffino and Mammucari, 2011), but detected developmental regulation of IGF2 (16-fold decline).”
BackgroundIdentification of novel pathways and immune profiles related to sarcopenia
Abdelrahman, Z., Wang, X., Wang, D., Zhang, T., Zhang, Y., Wang, X., & Chen, Z. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.928285 · Cited by 16
“Animal studies suggested that the PI3k-Akt pathway is strongly linked to muscle synthesis (3).”
BackgroundMechanisms of Ovarian Cancer-Associated Cachexia
Callaway, C. S., Mouchantat, L. M., Bitler, B. G., & Bonetto, A. (2023) · Endocrinology · doi:10.1210/endocr/bqad176 · Cited by 16
Hour, T., Nhi, N. T. L., Lai, I., Chuu, C., Lin, P., Chang, H., Su, Y., Chen, C., & Chen, Y. (2024) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202300685 · Cited by 16
Sex-dependent regulation of vertebrate somatic growth and aging by germ cells
Abe, K., Ino, H., Niwa, T., Semmy, D., Takaochi, A., Nishimura, T., Mogi, C., Uenaka, M., Ishii, M., Tanaka, K. Y., et al. (2024) · Science Advances · doi:10.1126/sciadv.adi1621 · Cited by 19
“3G) ( 27 ), were consistently down-regulated in germ cell–removed females (Fig.”
BackgroundJang, J., Yun, H.-Y., Park, J.-H., & Lim, K. (2015) · Physical Activity and Nutrition · doi:10.5717/jenb.2015.15062704 · Cited by 16
“Inversely, a crucial regulatory factor for protein synthesis, mTOR, is inhibited by the activation of FoxOs activation, leading to protein degradation [37-38].”
BackgroundOliveira, T. R. D. P., Manhães‐de‐Castro, R., Silva, J. M., Cadena-Burbano, E. V., Cavalcanti, C. C. L., Benjamim, R. D. A. C., Lago, A. B., Tourneur, Y., Antônio-Santos, J., & Aragão, R. D. S. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.11.011 · Cited by 16
“During postnatal development, the growth of muscle fibres involves the increase of myonuclei and hypertrophy, which are activated by some signalling pathways including obestatin, as cited above, and IGF-1-AKT-mTORpathway [37,41].”
BackgroundEndocrine regulation of regeneration: Linking global signals to local processes
Easterling, M. R., Engbrecht, K. M., & Crespi, E. J. (2019) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2019.113220 · Cited by 16
Weight-bearing exercise prevents skeletal muscle atrophy in ovariectomized rats
Tang, L., Cao, W., Zhao, T., Yu, K., Sun, L., Guo, J., Fan, X., & Ta, D. (2021) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-021-00794-0 · Cited by 18
Genome-wide DNA methylation analysis in Chinese Chenghua and Yorkshire pigs
Wang, K., Wu, P., Wang, S., Ji, X., Chen, D., Jiang, A., Xiao, W., Gu, Y., Jiang, Y., Zeng, Y., et al. (2021) · BMC Genomic Data · doi:10.1186/s12863-021-00977-0 · Cited by 15
Ciemiński, K., Flis, D. J., Dzik, K. P., Kaczor, J. J., Bialobrodzka, E. G., Hałoń, M., Wieckowski, M. R., Antosiewicz, J., & Ziółkowski, W. (2021) · Scientific Reports · doi:10.1038/s41598-021-00319-1 · Cited by 16
Akt-mediated phosphorylation controls the activity of the Y-box protein MSY3 in skeletal muscle
Angelis, L. D., Balasubramanian, S., & Berghella, L. (2015) · Skeletal Muscle · doi:10.1186/s13395-015-0043-9 · Cited by 14
From QTL to QTN: Candidate Gene Set Approach and a Case Study in Porcine IGF1-FoxO Pathway
Wang, M., Wang, Q., & Pan, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053452 · Cited by 16
“functional elements correlated with the model animals’ growth [22,23,24].”
BackgroundFortes, M. A. S., Scervino, M. V. M., Marzuca-Nassr, G. N., Vitzel, K. F., Pinheiro, C. H. D. J., & Curi, R. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00830 · Cited by 16
Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice
Tang, K., Pasqua, T., Biswas, A., Mahata, S., Tang, J., Tang, A., Bandyopadhyay, G. K., Sinha‐Hikim, A. P., Chi, N., Webster, N. J. G., et al. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0370 · Cited by 16
“The activation of satellite cells under the basal lamina of muscle fibers is accelerated by insulin-like growth factor-I and mechano-growth factor induced in exhausted muscles after training (Machida & Booth 2004, Schiaffino & Mammucari 2011).”
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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