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Insulin‐Like Growth Factor I Regulation and Its Actions in Skeletal Muscle

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ABSTRACT

The insulin‐like growth factor (IGF) pathway is essential for promoting growth and survival of virtually all tissues. It bears high homology to its related protein insulin, and as such, there is an interplay between these molecules with regard to their anabolic and metabolic functions. Skeletal muscle produces a significant proportion of IGF‐1, and is highly responsive to its actions, including increased muscle mass and improved regenerative capacity. In this overview, the regulation of IGF‐1 production, stability, and activity in skeletal muscle will be described. Second, the physiological significance of the forms of IGF‐1 produced will be discussed. Last, the interaction of IGF‐1 with other pathways will be addressed. © 2019 American Physiological Society. Compr Physiol 9:413‐438, 2019.

Figure 1. Figure 1. Primary sequence and structure of mature IGF‐1. (A) Sequence comparison of human IGF‐1 and proinsulin. Mature IGF‐1 has high homology with the related protein insulin. Boxed residues indicate identical sequence between the two proteins. Domains B (residues 3‐28), C (residues 29‐41), A (residues 42‐62), and D (residues 63‐70) are depicted with colored bands in blue, light yellow, pink, and light gray, respectively. The proinsulin sequence is used to include Domain C, which is cleaved in the formation of insulin. Adapted with permission from (). (B) A ribbon diagram of the 3D structure of IGF‐1. Domains are color coded as in A. In yellow are depicted the disulfide bonds (Cys 6‐Cys 48, Cys 18‐Cys 61, and Cys 47‐Cys 52). The dotted regions between Ser 34 and Thr 41 is flexible and not resolved in the first crystal structure. The D domain after Leu 64 is also flexible. Figure adapted with permission from [Felix F. Vajdos, Mark Ultsch, Michelle L. Schaffer, et al. ()]. Copyright (2018) American Chemical Society.
Figure 2. Figure 2. Schematic representation of human IGF1 gene, its alternative splicing events and their putative translational products. (A) IGF1 gene consists of six exons. Exons 1 and 2 contain multiple transcription initiation sites (TIS) (solid arrows). Translation initiation codons are located in exons 1, 2, and 3 (hollow arrows). The white portions of each exon represent the untranslated regions (UTRs). (B) Alternative splicing occurs both at 5′‐ and 3′‐ends of the gene and can give rise to various mRNA transcripts. Exons 1 and 2 are used interchangeably. Exon 4 is spliced to Exon 6 in most cases. However, Exon 4 can also be spliced to Exon 5. Further, an additional internal splice site in Exon 5 (shown as a break in the aqua portion of the Exon) can splice to Exon 6 causing a reading frame shift and a premature stop codon in the Exon 6 sequence, shown as a break in the orange portion of the Exon 6. (C) The resultant translational products include a signal peptide encoded by Exon 1, 3 (Class 1), Exons 2, 3 (Class 2), or in rare occasions Exon 3 (Class 3). The mature peptide is invariant and is encoded by portions of Exons 3 and 4 (in red). Last, the translational products include an E‐peptide consisting of the C‐terminal portion of Exon 4 (in purple) and Exon 6 in orange (Class Ea), or Exon 5 in aqua (Class Eb), or portions of Exons 5 and 6 (Class Ec). Exon 6 in Class Ec is shown in brown to indicate the frame shift that occurs with alternative splicing.
Figure 3. Figure 3. Posttranslational processing of IGF‐1. Human Pro‐IGF‐1 contains mature IGF‐1 and one of three E‐peptides (Ea, Eb, and Ec). All three pro‐forms share the B, C, A, and D domains of mature IGF‐1 (in red) and the first 16 amino acids of the E‐peptide (in purple). Alternative splicing results in the divergent sequences of the E‐peptides, which are color coded as described in Figure 2. The N‐terminus of the mature peptide contains a putative cleavage site for acid proteases that can give rise to des‐(1‐3)‐IGF‐1, following cleavage of the initial GPE (in bold). The residues (Lys68, Arg71, Arg74, and Arg77 in bold) are recognized by members of the proprotein convertase family, and are required for cleavage of the E peptides from the mature peptide. These sites are located in the sequence shared by all pro‐IGF‐1 forms. Grey arrows indicate sites for cleavage at the N‐terminus and between the mature and E‐peptides. In the human pro‐IGF‐1Ea, there is one glycosylation site Asn92 (in rodents there are two N‐glycosylation sites, Asn92 and Asn100).
Figure 4. Figure 4. Overview of the IGF‐1 system and its associated IGF‐1 receptor signaling pathway in skeletal muscle. IGF‐1 is found in the extracellular matrix as a complex with IGF binding proteins. Protease cleavage of the Binding proteins releases IGF‐1, which can then bind to IGF‐1 receptors (IGF‐1R). IGF‐1 also has high affinity for hybrid receptors (IGF‐1R/IR‐A and IGF‐1R/IR‐1B), but lower affinity for insulin receptors (IR‐A, IR‐B). Only the pathway associated with IGF‐1R is depicted for simplicity. Upon IGF‐1 binding to its receptor, the receptor tyrosine kinase is activated. Receptor activation results in phosphorylation of the IRS and SHC adaptor proteins and consequently leads to activation of PI3K/Akt/mTOR and RAF/MEK/ERK1/2 pathways, respectively. Akt phosphorylation leads to phosphorylation many substrates. mTOR phosphorylation causes it activation, which then phosphorylates p70s6 kinase (P70S6K) causing activation, the eukaryotic translation initiation factor 4E‐ binding protein (4E‐BP1) causing its inactivation, and also phosphorylated Akt at Ser473 causing maximal activation. Akt also phosphorylates Glycogen synthase kinase 3 beta (GSK3b) causing its inactivation, and as a result, disinhibits eukaryotic initiation factor 2B (elF2B). Akt also phosphorylates the forkhead box O transcription factors (FoXO) blocking its nuclear translocation and activation of expression of the E3 ubiquitin ligases, MURF1 and MAFbx. Negative feedback of the signaling pathway can occur, including the serine phosphorylation of IRS by P70S6K, causing its degradation. The MAPK arm of the signaling pathway is known to stimulate cell proliferation and regulation of gene expression, and as a hub kinase, is associated with multiple ligand‐receptor actions.


Figure 1. Primary sequence and structure of mature IGF‐1. (A) Sequence comparison of human IGF‐1 and proinsulin. Mature IGF‐1 has high homology with the related protein insulin. Boxed residues indicate identical sequence between the two proteins. Domains B (residues 3‐28), C (residues 29‐41), A (residues 42‐62), and D (residues 63‐70) are depicted with colored bands in blue, light yellow, pink, and light gray, respectively. The proinsulin sequence is used to include Domain C, which is cleaved in the formation of insulin. Adapted with permission from (). (B) A ribbon diagram of the 3D structure of IGF‐1. Domains are color coded as in A. In yellow are depicted the disulfide bonds (Cys 6‐Cys 48, Cys 18‐Cys 61, and Cys 47‐Cys 52). The dotted regions between Ser 34 and Thr 41 is flexible and not resolved in the first crystal structure. The D domain after Leu 64 is also flexible. Figure adapted with permission from [Felix F. Vajdos, Mark Ultsch, Michelle L. Schaffer, et al. ()]. Copyright (2018) American Chemical Society.


Figure 2. Schematic representation of human IGF1 gene, its alternative splicing events and their putative translational products. (A) IGF1 gene consists of six exons. Exons 1 and 2 contain multiple transcription initiation sites (TIS) (solid arrows). Translation initiation codons are located in exons 1, 2, and 3 (hollow arrows). The white portions of each exon represent the untranslated regions (UTRs). (B) Alternative splicing occurs both at 5′‐ and 3′‐ends of the gene and can give rise to various mRNA transcripts. Exons 1 and 2 are used interchangeably. Exon 4 is spliced to Exon 6 in most cases. However, Exon 4 can also be spliced to Exon 5. Further, an additional internal splice site in Exon 5 (shown as a break in the aqua portion of the Exon) can splice to Exon 6 causing a reading frame shift and a premature stop codon in the Exon 6 sequence, shown as a break in the orange portion of the Exon 6. (C) The resultant translational products include a signal peptide encoded by Exon 1, 3 (Class 1), Exons 2, 3 (Class 2), or in rare occasions Exon 3 (Class 3). The mature peptide is invariant and is encoded by portions of Exons 3 and 4 (in red). Last, the translational products include an E‐peptide consisting of the C‐terminal portion of Exon 4 (in purple) and Exon 6 in orange (Class Ea), or Exon 5 in aqua (Class Eb), or portions of Exons 5 and 6 (Class Ec). Exon 6 in Class Ec is shown in brown to indicate the frame shift that occurs with alternative splicing.


Figure 3. Posttranslational processing of IGF‐1. Human Pro‐IGF‐1 contains mature IGF‐1 and one of three E‐peptides (Ea, Eb, and Ec). All three pro‐forms share the B, C, A, and D domains of mature IGF‐1 (in red) and the first 16 amino acids of the E‐peptide (in purple). Alternative splicing results in the divergent sequences of the E‐peptides, which are color coded as described in Figure 2. The N‐terminus of the mature peptide contains a putative cleavage site for acid proteases that can give rise to des‐(1‐3)‐IGF‐1, following cleavage of the initial GPE (in bold). The residues (Lys68, Arg71, Arg74, and Arg77 in bold) are recognized by members of the proprotein convertase family, and are required for cleavage of the E peptides from the mature peptide. These sites are located in the sequence shared by all pro‐IGF‐1 forms. Grey arrows indicate sites for cleavage at the N‐terminus and between the mature and E‐peptides. In the human pro‐IGF‐1Ea, there is one glycosylation site Asn92 (in rodents there are two N‐glycosylation sites, Asn92 and Asn100).


Figure 4. Overview of the IGF‐1 system and its associated IGF‐1 receptor signaling pathway in skeletal muscle. IGF‐1 is found in the extracellular matrix as a complex with IGF binding proteins. Protease cleavage of the Binding proteins releases IGF‐1, which can then bind to IGF‐1 receptors (IGF‐1R). IGF‐1 also has high affinity for hybrid receptors (IGF‐1R/IR‐A and IGF‐1R/IR‐1B), but lower affinity for insulin receptors (IR‐A, IR‐B). Only the pathway associated with IGF‐1R is depicted for simplicity. Upon IGF‐1 binding to its receptor, the receptor tyrosine kinase is activated. Receptor activation results in phosphorylation of the IRS and SHC adaptor proteins and consequently leads to activation of PI3K/Akt/mTOR and RAF/MEK/ERK1/2 pathways, respectively. Akt phosphorylation leads to phosphorylation many substrates. mTOR phosphorylation causes it activation, which then phosphorylates p70s6 kinase (P70S6K) causing activation, the eukaryotic translation initiation factor 4E‐ binding protein (4E‐BP1) causing its inactivation, and also phosphorylated Akt at Ser473 causing maximal activation. Akt also phosphorylates Glycogen synthase kinase 3 beta (GSK3b) causing its inactivation, and as a result, disinhibits eukaryotic initiation factor 2B (elF2B). Akt also phosphorylates the forkhead box O transcription factors (FoXO) blocking its nuclear translocation and activation of expression of the E3 ubiquitin ligases, MURF1 and MAFbx. Negative feedback of the signaling pathway can occur, including the serine phosphorylation of IRS by P70S6K, causing its degradation. The MAPK arm of the signaling pathway is known to stimulate cell proliferation and regulation of gene expression, and as a hub kinase, is associated with multiple ligand‐receptor actions.
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Teaching Material

G. Vassilakos, E. R. Barton. Insulin-Like Growth Factor I Regulation and Its Actions in Skeletal Muscle. Compr Physiol 9: 2019, 443-468.

Didactic Synopsis

Major Teaching Points:

  • IGF-1 and insulin are highly related molecules with similar and divergent actions.
  • The regulation of IGF-1 production occurs at both the transcriptional and translational levels.
    • Alternative splicing generates multiple forms of IGF-1
    • Protease cleavage and protein modifications happen after translation of IGF-1
  • The forms are different and the C-terminal end of the protein, producing multiple E-peptides, which have potential, but controversial, functional significance.
  • IGF-1 signal transduction drives both increased protein synthesis, protection against degradative pathways, and negative feedback to tune IGF-1 activity.
  • IGF-1 availability is modulated by many extracellular proteins.
  • The IGF-1 signaling pathway interacts with other growth factors.
  • IGF-1 regulates both growth (anabolic actions) and glucose (metabolic actions).

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching points: The IGF-1 and insulin proteins are related both in primary sequence and in their structure. One of the main divergent features is that IGF-1 retains the C domain, which is removed from proinsulin when it is processed to generate mature insulin.

Figure 2 Teaching points: For such a small protein, IGF-1 has very complex transcriptional regulation. The major point of this figure is to illustrate this complexity, including the alternative splicing, the multiple transcriptional initiation sites, and the different classes of peptides that result. It is important to recognize that all forms that are produced share a common mature IGF-1 sequence.

Figure 3 Teaching points: This is a continuation from Figure 2, showing how the peptides that get translated are subjected to more post-translational processing. This includes several proteases that can separate the mature IGF-1 peptide from the C-terminal E peptides, and also “trim” the mature peptide. It also includes the N-glycosylation that can occur in the major IGF-1Ea form, which is the predominant form in skeletal muscle.

Figure 4 Teaching points: The IGF-1 signaling pathway shown is the major arm through the IGF-1 receptor. The figure shows the general features of the pathway, including the serial phosphorylation by many kinases in the pathway. In some cases, the phosphorylation activate the downstream target, such as in the Ras/Raf/MEK/Erk1/2 arm. In other cases, the phosphorylation inactivates the target, such as with Akt phosphorylation of GSK3b or FoXO. Of note, is the presence of IGFBPs outside of the cell, which bind to IGF-1, keeping is stored, but also preventing it from binding to receptors.

 


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How to Cite

Georgios Vassilakos, Elisabeth R. Barton. Insulin‐Like Growth Factor I Regulation and Its Actions in Skeletal Muscle. Compr Physiol 2018, 9: 413-438. doi: 10.1002/cphy.c180010