The ABCs of IGF-I isoforms: impact on muscle hypertrophy and implications for repair

Barton, Elisabeth R.

doi:10.1139/h06-054

Cited by 119 publications

(119 citation statements)

References 38 publications

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“…Although there is a single form of mature ligand (B-C-A-D domains), the isoforms of IGF1 precursor (signal peptide and domains B-C-A-D-E) differ in the sequences of the preregion and the E domain, which are removed by proteolytic processing (for a review see ref. 15). The particular cDNA sequence that we have used represents only one version of E domain and the encoded signal peptide is destined to be truncated (starting at an internal methionine codon; see Fig.…”

Section: Resultsmentioning

confidence: 99%

The hormonal action of IGF1 in postnatal mouse growth

Στρατικόπουλος

Szabolcs²,

Dragatsis

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

189

129

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The mammalian insulin-like growth factor 1 (IGF1), which is a member of a major growth-promoting signaling system, is produced by many tissues and functions throughout embryonic and postnatal development in an autocrine/paracrine fashion. In addition to this local action, IGF1 secreted by the liver and circulating in the plasma presumably acts systemically as a classical hormone. However, an endocrine role of IGF1 in growth control was disputed on the basis of the results of a conditional, liver-specific Igf1 gene knockout in mice, which reduced significantly the level of serum IGF1, but did not affect average body weight. Because alternate interpretations of these negative data were tenable, we addressed genetically the question of hormonal IGF1 action by using a positive experimental strategy based on the features of the cre/ loxP recombination system. Thus, we generated bitransgenic mice carrying in an Igf1 null background a dormant Igf1 cDNA placed downstream of a transcriptional ''stop'' DNA sequence flanked by loxP sites (floxed) and also a cre transgene driven by a liver-specific promoter. The Igf1 cDNA, which was inserted by knock-in into the mutated and inactive Igf1 locus itself to ensure proper transcriptional regulation, was conditionally expressed from cognate promoters exclusively in the liver after Cre-mediated excision of the floxed block. Our genetic study demonstrated that the endocrine IGF1 plays a very significant role in mouse growth, as its action contributes approximately30% of the adult body size and sustains postnatal development, including the reproductive functions of both mouse sexes.gene targeting ͉ T he insulin-like growth factor (IGF) signaling system is the major determinant of mammalian organismal growth, as it provides the main common downstream conduit for the action of most growth-promoting gene products controlling body size (1, 2). IGF1 is one of the ligands of this family of effectors that is produced by many tissues and acts in an autocrine/paracrine fashion. In addition, it circulates in the plasma associated with binding proteins (IGFBPs). Classically, it was thought that the circulating IGF1, which postnatally is produced in the liver under growth hormone (GH) control, acts systemically as a hormone. In 1999, however, two groups using the same conditional Igf1 gene mutation in mice challenged the view of endocrine IGF1 effects (3, 4). Specifically, the apparent lack of effects on average body weight and length after liver-specific ablation of floxed Igf1 exon 4 using either an albumincre or an Mx1-cre transgene, which led to a markedly reduced level of circulating factor, was interpreted as demonstrating that liverderived IGF1 is not required for postnatal growth. The albumin-cre mediated DNA excision appeared to be nearly complete in adult liver IGF1-deficient (LID) mice, but residual IGF1 (reportedly 25% of the normal level) thought to be produced by an unknown extrahepatic source was detected in serum.In our view, however, the question about an endocrine IGF1 functio...

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Section: Resultsmentioning

confidence: 99%

The hormonal action of IGF1 in postnatal mouse growth

Στρατικόπουλος

Szabolcs²,

Dragatsis

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

189

129

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“…Two prominent signaling molecules, insulin-like growth factor 1 (IGF1) and myostatin (MSTN), were previously implicated in regulating skeletal muscle growth (47,48). IGF1 positively regulates muscle mass through the PI3K and AKT pathway, whereas MSTN acts as a negative regulator by regulating the SMAD pathway.…”

Section: Discussionmentioning

confidence: 99%

A WNT/β-Catenin Signaling Activator, R-spondin, Plays Positive Regulatory Roles during Skeletal Myogenesis

Han

Jin

Seto

et al. 2011

Journal of Biological Chemistry

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R-spondins (RSPOs) are a recently characterized family of secreted proteins that activate WNT/␤-catenin signaling. In this study, we investigated the potential roles of the RSPO proteins during myogenic differentiation. Overexpression of the Rspo1 gene or administration of recombinant RSPO2 protein enhanced mRNA and protein expression of a basic helix-loophelix (bHLH) class myogenic determination factor, MYF5, in both C2C12 myoblasts and primary satellite cells, whereas MYOD or PAX7 expression was not affected. RSPOs also promoted myogenic differentiation and induced hypertrophic myotube formation in C2C12 cells. In addition, Rspo2 and Rspo3 gene knockdown by RNA interference significantly compromised MYF5 expression, myogenic differentiation, and myotube formation. Furthermore, Myf5 expression was reduced in the developing limbs of mouse embryos lacking the Rspo2 gene. Finally, we demonstrated that blocking of WNT/␤-catenin signaling by DKK1 or a dominant-negative form of TCF4 reversed MYF5 expression, myogenic differentiation, and hypertrophic myotube formation induced by RSPO2, indicating that RSPO2 exerts its activity through the WNT/␤-catenin signaling pathway. Our results provide strong evidence that RSPOs are key positive regulators of skeletal myogenesis acting through the WNT/␤-catenin signaling pathway.WNT signaling plays diverse roles in normal tissue development during embryogenesis and tissue function in adulthood. The importance of WNT signaling in skeletal myogenesis was initially demonstrated in embryonic skeletal myogenesis (1-4). The WNT1 and WNT3A ligands derived from the dorsal neural tube and the surface ectoderm positively regulate skeletal myogenesis within somites via the canonical WNT/␤-catenin signaling pathway (3, 4). Furthermore, noncanonical WNT signaling, which transmits signals through the RAC/RHO-dependent planar cell polarity and calcium-PKC pathways, regulates PAX3 and subsequently MYOD expression during myogenic differentiation (5) and a directional elongation of myofibers within the myotome (6).Recently, progress has been made in the understanding of the roles of WNT signaling in postnatal myogenesis. For instance, ␤-catenin was shown to promote self-renewal of satellite cells, the muscle stem/progenitor cells residing in adult skeletal muscle (7). In contrast, WNT/␤-catenin signaling was shown to initiate myogenic differentiation of satellite cells by replacing NOTCH signaling, which is critical for self-renewal of satellite cells, through the inhibition of GSK-3␤ (8). It was also demonstrated that the activation of the WNT/␤-catenin pathway occurs within the CD45-positive stem cell population present in regenerating skeletal muscles but not in satellite cells (9). In aged skeletal muscle, WNT10B regulates the balance between myogenic and adipogenic lineage determination (10). WNT signaling was also suggested to induce a fibroblastic phenotype in aged skeletal muscle (11). Furthermore, WNT7A regulates self-renewal of satellite cells via noncanonical WNT signaling (12). These ...

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“…These multiple IGF-I transcripts code different precursor polypeptides, which also undergo posttranslational modifications (26,43,44), (Figures 1A-C).…”

Section: Human Igf1 Gene Structure and Alternative Splicingmentioning

confidence: 99%

“…IGF-I mediates its actions through the binding and activation of several receptors and the IGF-I domain which is responsible for the receptor binding is the biologically active mature peptide. It is derived after the posttranslational cleavage of the pro-IGF-I (iso)forms and the removal of the E-peptides (23)(24)(25)(26). Interestingly, it has been proposed that the E-peptides also possess bioactivity that is distinct from that of mature IGF-I (20,27).…”

Section: Introductionmentioning

confidence: 99%

The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

Philippou

Maridaki

Pneumaticos

et al. 2014

Mol Med

100

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The insulinlike growth factor-I (IGF-I) is an important factor which regulates a variety of cellular responses in multiple biological systems. The IGF1 gene comprises a highly conserved sequence and contains six exons, which give rise to heterogeneous mRNA transcripts by a combination of multiple transcription initiation sites and alternative splicing. These multiple transcripts code for different precursor IGF-I polypeptides, namely the IGF-IEa, IGF-IEb and IGF-IEc isoforms in humans, which also undergo posttranslational modifications, such as proteolytic processing and glycosylation. IGF-I actions are mediated through its binding to several cell-membrane receptors and the IGF-I domain responsible for the receptor binding is the bioactive mature IGF-I peptide, which is derived after the posttranslational cleavage of the pro-IGF-I isoforms and the removal of their carboxy-terminal E-peptides (that is, the Ea, Eb and Ec). Interestingly, differential biological activities have been reported for the different IGF-I isoforms, or for their E-peptides, implying that IGF-I peptides other than the IGF-I ligand also possess bioactivity and, thus, both common and unique or complementary pathways exist for the IGF-I isoforms to promote biological effects. The multiple peptides derived from IGF-I and the differential expression of its various transcripts in different conditions and pathologies appear to be compatible with the distinct cellular responses observed to the different IGF-I peptides and with the concept of a complex and possibly isoform-specific IGF-I bioactivity. This concept is discussed in the present review, in the context of the broad range of modifications that this growth factor undergoes which might regulate its mechanism(s) of action.

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The ABCs of IGF-I isoforms: impact on muscle hypertrophy and implications for repair

Cited by 119 publications

References 38 publications

The hormonal action of IGF1 in postnatal mouse growth

The hormonal action of IGF1 in postnatal mouse growth

A WNT/β-Catenin Signaling Activator, R-spondin, Plays Positive Regulatory Roles during Skeletal Myogenesis

The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

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