Abstract
Insulin-like growth factor-1 (IGF-1), a 70-amino-acid polypeptide hormone structurally similar to proinsulin, mediates endocrine, paracrine, and autocrine signaling to orchestrate cellular proliferation, differentiation, and survival across diverse tissues. Predominantly synthesized in the liver under growth hormone (GH) stimulation, IGF-1 circulates bound to IGF-binding proteins (IGFBPs), with IGFBP-3 accounting for the majority of complexes.
Introduction
The somatotropic axis, encompassing hypothalamic-pituitary orchestration of GH release and peripheral IGF-1 generation, constitutes a pivotal endocrine network governing postnatal growth, metabolic partitioning, and tissue maintenance. IGF-1 serves as the principal effector, transducing GH signals into cellular actions.
Age-related IGF-1 trajectories exhibit biphasic patterns: peak circulating levels in adolescence, followed by decline of approximately 1-2% annually post-40 years—mirroring growth hormone decline in what is termed the "somatopause."
Molecular Background
IGF-1 comprises 70 residues arranged in three domains with three intrachain disulfide bridges, conferring ~50% sequence identity to insulin. Key aspects include:
- Biosynthesis: Primarily hepatic via GH-stimulated JAK2-STAT5b pathway
- Paracrine production: Skeletal muscle (via MRFs), bone (via Runx2)
- Circulating levels: ~150-300 ng/mL in adults
- Binding: ~99% bound to IGFBPs; IGFBP-3 sequesters ~80%
Mechanisms of Action
AMPK Interactions
IGF-1 interfaces with AMPK antagonistically, as anabolic flux suppresses energetic vigilance. In myocytes, IGF-1 attenuates AICAR-induced AMPKα phosphorylation via AKT crosstalk.
SIRT1 Pathway
IGF-1-induced AKT phosphorylates FOXO1/3, exporting them from nuclei and modulating SIRT1-mediated deacetylation. In neuronal cultures, IGF-1 may elevate NAD⁺ pools indirectly via glycolysis.
mTOR Activation
Central to IGF-1 signaling is mTOR activation. The IGF-1R-IRS-PI3K cascade elevates PIP3, recruiting PDK1 to phosphorylate AKT, which inactivates TSC2, liberating Rheb-GTP for mTORC1 assembly. This amplifies translation of ribosomal proteins with ~3-fold protein synthesis increases in vitro.
FOXO3 Sequestration
AKT-mediated multisite phosphorylation of FOXO3 promotes 14-3-3 binding, preventing transactivation of atrophy genes like MAFbx/atrogin-1 and MuRF1.
NRF2 Enhancement
PI3K/AKT stabilizes NRF2 via KEAP1 phosphorylation, facilitating nuclear translocation and ARE binding for antioxidant gene induction.
Metabolic and Physiological Roles
- Glucose metabolism: GLUT4 translocation increases glucose uptake ~40%
- Protein synthesis: Leucine incorporation increases ~50% post-stimulation
- Bone: Stimulates preosteoblast replication, inhibits osteoclastogenesis
- Muscle: Satellite cell activation and type II fiber hypertrophy
- Neurotrophy: Promotes hippocampal neurogenesis
Preclinical Research
In Vitro Studies
- L6 myoblasts: 10 nM IGF-1 accelerates proliferation via cyclin D1/2
- Myotube cultures: 2-3-fold hypertrophy with myostatin suppression
- MC3T3-E1 osteoblasts: ALP/OCN transcripts doubled, mineralization +150%
- PC12 neurons: Neurite outgrowth ~4-fold
Animal Models
- GH-deficient mice (IGF-1 infusion): +25% lean mass, soleus fiber area +30%, grip +40%
- Ovariectomized rats: Vertebral BMD +8% preservation
- Hindlimb suspension: 50% atrophy reversal with local IGF-1
- Aged C57BL/6: Morris water maze latencies halved, hippocampal volume +15%
- Diabetic wound healing: 60% faster closure in db/db mice
Human Research
- Cross-sectional (NHANES): Low IGF-1 (<100 ng/mL) associated with sarcopenia odds ratio of 2.5
- Elderly men trial (n=21, 6 months): +8.8% fat-free mass, -14.4% fat mass, +1.6% lumbar BMD
- Postmenopausal women (n=30, 12 months): BMD gains +2.3% at hip
- Exercise interventions: Resistance training elevates muscle IGF-1 mRNA 3-fold
Safety Considerations
Preclinical doses (0.1-5 mg/kg) show no acute toxicity. Human trials report dose-dependent hypoglycemia (10-20%), edema, and arthralgias. Long-term surveillance data for augmented states remain limited.
Summary Table
| Aspect | Key Findings | Model |
|---|---|---|
| mTOR Activation | +50% protein synthesis | C2C12 myotubes |
| Aging/Sarcopenia | +8.8% lean mass | Elderly men (n=21) |
| Bone Density | Trabecular volume +8% | OVX rats |
| Muscle Hypertrophy | Fiber CSA +30% | GH-def mice |
| Human Decline | 1-2%/year post-40 | NHANES cohorts |
Conclusion
IGF-1 serves as the somatotropic axis's principal anabolic effector, transducing growth hormone signals into proliferative and trophic cascades. Its bioavailability—regulated by IGFBPs—calibrates responses across muscle, bone, and neural tissues.
The mechanistic framework of PI3K/mTOR activation and FOXO3 suppression manifests physiologically as muscle accrual and skeletal fortification. While age-related decline correlates with sarcopenic and osteoporotic phenotypes, the dual nature of IGF-1—anabolic benefits versus proliferative considerations—requires careful evaluation in research contexts.