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IGF-1-Mediated Skeletal Muscle Hypertrophy via PI3K/Akt/mTOR Signaling
Rommel et al. (2001) demonstrated that IGF-1-induced skeletal myotube hypertrophy is mediated by two distinct signaling cascades: PI3K/Akt/mTOR and PI3K/Akt/GSK3β. Using differentiated C2C12 myotubes as a model system, the researchers showed that IGF-1 stimulates protein synthesis and increases myotube diameter through activation of Akt (protein kinase B), which subsequently activates mammalian target of rapamycin (mTOR) and inhibits glycogen synthase kinase 3β (GSK3β). Blocking either pathway with selective inhibitors (rapamycin for mTOR, lithium chloride for GSK3β) partially prevented hypertrophy, establishing that both arms of the PI3K/Akt axis are required for the full anabolic effect of IGF-1.
Citation: Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L, Stitt TN, Yancopoulos GD, Glass DJ. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol. 2001;3(11):1009-1013. doi:10.1038/ncb1101-1009. PubMed PMID: 11715022
Contribution of Satellite Cells to IGF-I-Induced Muscle Hypertrophy
Barton-Davis et al. (1999) investigated the role of satellite cells in mediating the hypertrophic effects of IGF-I in skeletal muscle. Using viral-mediated gene transfer to overexpress IGF-I in mouse hindlimb muscles, the researchers observed significant increases in muscle mass and strength compared to controls. The study demonstrated that IGF-I-induced functional hypertrophy is achieved via a combination of satellite cell activation — leading to increased muscle regeneration — and direct stimulation of protein synthesis in differentiated myofibers. This dual mechanism established IGF-I as a key factor coordinating both stem cell recruitment and protein accretion in skeletal muscle growth.
Citation: Barton-Davis ER, Shoturma DI, Sweeney HL. Contribution of satellite cells to IGF-I induced hypertrophy of skeletal muscle. Acta Physiol Scand. 1999;167(4):301-305. doi:10.1046/j.1365-201x.1999.00618.x. PubMed PMID: 10632630
Comprehensive Review: Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle
Yoshida and Bhimani (2020) published a comprehensive review of the mechanisms by which IGF-1 regulates both anabolic and catabolic pathways in skeletal muscle. The review detailed how IGF-1 increases skeletal muscle protein synthesis via PI3K/Akt/mTOR and PI3K/Akt/GSK3β pathways, while simultaneously inhibiting protein degradation through suppression of FoxO-dependent transcription of E3 ubiquitin ligases (atrogin-1/MAFbx and MuRF1). The authors also discussed how IGF-1 signaling can activate satellite cells, contributing to muscle repair and growth, and how various IGF-1 isoforms including mechano-growth factor (MGF) and modified analogs with reduced IGFBP binding may have enhanced bioactivity in skeletal muscle tissue.
Citation: Yoshida T, Delafontaine P. Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy. Cells. 2020;9(9):1970. doi:10.3390/cells9091970. PubMed PMID: 32858949
IGF-1 Monitoring in Medical Diagnostics and Sports Science
Pokrywka et al. (2021) published a comprehensive review examining IGF-1 and its analogs — including IGF-1 LR3 — in the context of medical diagnostics and sports science. The authors detailed how Long R3 IGF-1 (IGF-1 LR3) is a recombinant analogue with an arginine substitution at amino acid three and an additional thirteen amino acids at its N-terminus. These modifications result in markedly reduced affinity for IGF-binding proteins, effectively increasing the fraction of biologically active (free) IGF-1 available for receptor binding. The review discussed how this enhanced potency — estimated at 2–3 fold greater than native IGF-1 in cell proliferation assays — is attributed to the extended circulating half-life and reduced sequestration by binding proteins.
Citation: Pokrywka A, Cholbinski P, Kaliszewski P, Kowalczyk K, Konczak D, Zembron-Lacny A. Insulin-Like Growth Factor-1 (IGF-1) and Its Monitoring in Medical Diagnostic and in Sports. Biomolecules. 2021;11(2):217. doi:10.3390/biom11020217. PubMed PMID: 33557137
Extrapancreatic Incretin Receptors and IGF-1 Axis in Glucose Homeostasis
Hansotia et al. (2007) investigated the importance of endogenous incretin receptor signaling in extrapancreatic tissues for the control of glucose homeostasis, body weight, and energy expenditure using knockout mouse models. While focused on incretin receptors, this study provided important context for understanding the broader IGF-1 signaling axis. The researchers found that incretin receptor knockout mice exhibited resistance to diet-induced obesity and preservation of insulin sensitivity — phenotypic changes that involve cross-talk with the IGF-1/insulin receptor signaling network. The study demonstrated that metabolic regulation through growth factor and incretin pathways involves complex extrapancreatic tissue interactions relevant to IGF-1 biology.
Citation: Hansotia T, Maida A, Flock G, Yamada Y, Tsukiyama K, Seino Y, Drucker DJ. Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J Clin Invest. 2007;117(1):143-152. doi:10.1172/JCI25483. PubMed PMID: 17187081
Reviewed for scientific accuracy — Chameleon Peptides Research Team. Last reviewed: March 2026.