Role of IGF-I signaling in muscle bone interactions

Abstract

Skeletal muscle and bone rely on a number of growth factors to undergo development, modulate growth, and maintain physiological strength. A major player in these actions is insulin-like growth factor I (IGF-I). However, because this growth factor can directly enhance muscle mass and bone density, it alters the state of the musculoskeletal system indirectly through mechanical crosstalk between these two organ systems. Thus, there are clearly synergistic actions of IGF-I that extend beyond the direct activity through its receptor. This review will cover the production and signaling of IGF-I as it pertains to muscle and bone, the chemical and mechanical influences that arise from IGF-I activity, and the potential for therapeutic strategies based on IGF-I. This article is part of a Special Issue entitled "Muscle Bone Interactions".

Keywords: Bone density; Insulin-like growth factor; Muscle hypertrophy; Regeneration; Repair.

Figure 1

Alternative splicing of the Igf1 gene in rodents and humans. A. The 6 exons in Igf1 exhibit alternative splicing at the 5′ and 3′ ends, with exons 1 or 2 plus a portion of 3 encoding two classes of signal peptides. Exons 3 and 4 are invariant, containing the sequence for mature IGF-I. The remaining sequence generates the E peptide regions. B. Variants generated by splicing of exons 4 and exon 6 are referred to as IGF-IA. In humans, retention of the entire exon 5 sequence in the absence of exon 6 is referred to as IGF-IB. Transcripts that contain exons 4, 5 and 6 are designated as IGF-IC in humans, and IGF-IB in rodents. This form is also known as MGF.

Figure 2

Post-translational processing of IGF-I. A. Following translation of the pre-pro-peptide, which consists of a signal peptide directing secretion, the mature IGF-I peptide, and a C-terminal E-peptide extension, the signal peptide is cleaved to release pro-IGF-I (mature IGF-I plus an E-peptide). Pro-IGF-I can be subjected to cleavage of the E-peptide by intracellular proteases of the pro-protein convertase family to produce mature IGF-I for secretion, or secreted without cleavage. In addition, N-glycosylation in the E-peptide of the predominant IGF-I isoform (IGF-IA) can occur followed by secretion. B. Multiple forms of IGF-I protein exist in the extracellular milieu: mature IGF-I, non-glycosylated pro-IGF-I, and glycosylated-pro-IGF-I. Immunoblotting of lysates from liver (Liv), serum (Ser), and muscle (Mus) display the range of endogenous IGF-I species compared to recombinant mature IGF-I (IGF).

Figure 3. IGF1 signaling

The IGF1R is comprised of two α and 2 β subunits. On binding to IGF1, the cytoplasmic portion of the β subunits undergo phosphorylation at specific tyrosines, forming binding sites for a number of signaling molecules. The Shc/Grb2/SOS complex activates Ras leading to activation of the MAPK pathway. ERK1/2 phosphorylation enables these molecules to enter the nucleus to activate various transcription factors such as Jun/Fos. IRS-1 when phosphorylated can facilitate the activation of PI3K that leads in turn to PIP2 phosphorylation to PIP3, which brings PDK2 and AKT to the membrane where AKT is phosphorylated and activated. AKT has a number of substrates including BAD that when phosphorylated inactivates this proapoptotic molecule, mTOR which stimulates protein synthesis by activating p70^sk6, and FOXO which when phosphorylated is prevented from entering the nucleus and stimulating various ubiquitin ligases such as atrogin-1/MAFbx. AKT can also phosphorylate and inactivate GSK-3β, an important regulator of wnt/β-catenin signaling.