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The ABCs of IGF-I isoforms: impact on muscle

hypertrophy and implications for repair
Elisabeth R. Barton

Abstract: Insulin-like growth factor I (IGF-I) plays a critical role in the growth and development of many tissues in the
body. It is a key regulator of skeletal muscle development, and continues to enhance the ability for muscle to grow and
undergo repair throughout life. Although the focus of research has been on the molecular actions and physiological impact
of IGF-I, there has also been a growing undercurrent of studies geared toward the characterization of additional potentially
active peptides produced by the igf1 gene. Alternative splicing of the gene results in multiple isoforms that retain the iden-
tical sequence for mature IGF-I, but also give rise to divergent C-terminal peptides. The peptides might modulate the ac-
tions, stability, or bioavailability of IGF-I, or they might have independent activity. These possibilities have gained the
attention of the skeletal muscle field, where novel actions of IGF-I could have significant impact on muscle mass, strength,
and repair.
Key words: MGF, E peptides, satellite cells, recombinant adeno-associated virus, AAV, plasmid delivery.
Résumé : Le facteur de croissance insulinomimétique de type I (IGF-I) joue un rôle de premier plan dans la croissance et
le développement de nombreux tissus dans l’organisme. Ce facteur est un régulateur clé du développement du muscle
squelettique et un facilitateur de l’aptitude du muscle à se développer et à se réparer tout au long de la vie. Bien que les
études scientifiques aient surtout porté sur les actions moléculaires et les répercussions physiologiques de l’IGF-I, certaines
études ont cependant mis l’accent sur la caractérisation d’autres peptides potentiellement actifs produits par le gène igf1.
L’épissage alternatif du gène donne de multiples isoformes qui retiennent la même séquence pour un IGF-I mature mais
produit aussi des peptides C-terminal divergents. Les peptides peuvent moduler les actions, la stabilité ou la biodisponibi-
lité de l’IGF-I ou peuvent présenter une activité indépendante. Ces possibilités retiennent l’attention et font l’objet d’études
sur les muscles squelettiques qui, par les nouvelles actions de l’IGF-I, peuvent avoir un impact significatif sur la masse
musculaire, la force et l’aptitude à se régénérer.
Mots clés : MGF, peptide E, cellules satellites, adénovirus recombinant utilisé comme vecteur, AAV, transfert de plas-
[Traduit par la Rédaction]

Introduction IR) do not survive after birth (Baker et al. 1993; Liu et al.
1993). However, in another animal model, in which only
Insulin-like growth factor I (IGF-I) is essential for normal liver IGF-I expression was eliminated after birth, animals
growth and development. It is the major mediator of the showed no significant impairment to body growth (Sjogren
post-natal growth-promoting actions of growth hormone et al. 1999). Thus, local tissue production of IGF-I is suffi-
(GH). The predominant source of IGF-I is the liver, which cient to support normal growth of those tissues.
supplies approximately 75% of total circulating IGF-I for
the body (Schwander et al. 1983). However, other tissues,
including muscle, brain, and kidney, also express and pro-
IGF-I function in muscle
duce IGF-I. The necessity of IGF-I for normal growth of an Multiple methods have been used in animals to demon-
animal has been demonstrated in animal knockout models. strate that IGF-I mediates skeletal muscle hypertrophy, in-
Animals that cannot express IGF-I exhibit severe growth re- cluding infusion of recombinant protein and overexpression
tardation, and animals that do not express its receptor (IGF- of the gene encoding IGF-I (Adams and McCue 1998;
Barton-Davis et al. 1998;Coleman et al. 1995; Musaro et
Received 11 April 2006. Accepted 9 May 2006. Published on al. 2001). IGF-I increases muscle mass and strength in
the NRC Research Press Web site at http://apnm.nrc.ca on two main ways. First, IGF-I acts directly on the muscle fi-
12 December 2006. bers to increase protein synthesis and muscle mass. It also
E.R. Barton. Department of Anatomy and Cell Biology, School drives activated satellite cells (a stem cell like population
of Dental Medicine, and Pennsylvania Muscle Institute, residing close to muscle fibers and a source for replenish-
University of Pennsylvania, Philadelphia, PA 19104, USA. ing nuclear content of the muscle) to fuse to existing
e-mail: erbarton@biochem.dental.upenn.edu. muscle fibers, helping to repair damaged regions of the fi-

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792 Appl. Physiol. Nutr. Metab. Vol. 31, 2006

bers and promote muscle growth (Florini et al. 1993). This Fig. 1. Alternative splicing of the igf1 gene. The rodent gene has 6
process is very similar to that which occurs during muscle exons (A). Classes 1 and 2 arise from exon 1 or 2, respectively.
development, in which myoblast fusion and differentiation Class A transcripts exclude exon 5, whereas class B transcripts in-
is regulated by IGF-I. The binding of IGF-I to the IGF-I clude exon 5, which causes a frame shift and premature termination
receptor causes autophosphorylation on multiple tyrosine in exon 6. The human gene also has 6 exons (panel B), where class
residues, which, in turn, instigates a cascade of intracellu- 1 and 2 arise from splicing patterns similar to the rodent gene.
lar signaling events. Through the adaptor proteins, grb2 and Class A transcripts exclude exon 5, and class B transcripts exclude
mSos, the ras–raf-1–MEK–Erk pathway is stimulated, and exon 6. Class C is produced by an internal splice site within exon
has been shown to mediate proliferation (Coolican et al. 5, which causes a frame shift and premature termination in exon 6.
1997). Muscle cell culture studies have also confirmed The resultant peptide bears high homology to rodent class B IGF-I.
that the presence of IGF-I drives the phosphoinositol-3-kin-
ase (PI-3K) pathway, particularly at the inception of differ-
entiation (Coolican et al. 1997; Musaro et al. 1999). Owing
to this ability for IGF-I to regulate the development and
repair processes of muscle and of other tissues, it has
undergone intense study to characterize its involvement in
these processes and the regulation of IGF-I expression. It
is a potential candidate for a therapeutic agent, both in
aging and muscle disease, because it is able to aid in the
repair and maintenance of tissue health. Furthermore, it
has gained the attention of the athletic community as a
way to enhance the gains of mass and strength produced
by resistance training (Lee et al. 2004; Sweeney 2004).

igf1 gene structure

IGF-I is highly conserved in the animal kingdom. The ge-
netic sequence has been determined in a number of species,
including human, rat, chicken, sheep, and salmon (Adamo et
al. 1993; Lund 1998). Although there has been conservation
of the apparent gene structure, alternative splicing that oc-
curs at the 5’ and 3’ ends of the gene give rise to several
splice forms or isoforms, and the ways in which these arise
are not consistent across species. Needless to say, the
‘‘ABCs’’ for the nomenclature for IGF-I isoforms have im-
peded the progress of spelling out the functional differences
between them. However, it is intriguing that the alternative
splicing events have also been conserved across species,
even though the resultant IGF-I protein for which the gene
is named remains constant in all splice variants, and is
thought to act via the same IGF-I receptor.
The differences between human and rodent igf1 gene level. The human gene also has 6 exons, although exon 5 is
structure illustrates this point. There are 6 exons in the ro- significantly longer (515 nucleotides) (Rotwein et al. 1986).
dent igf1 gene spanning 80–100 kb (Fig. 1A) (Shimatsu and As in rodents, human class A IGF-I contains only exon 6 at
Rotwein 1987). Exons 1 and 2 are used interchangeably, and the 3’ end of the transcript (Fig. 1B). Class B, however, con-
constitute classes 1 and 2, respectively, of the IGF-I iso- tains only exon 5, resulting in unique E peptide extension
forms. These encode the 5’ untranslated region (UTR), and that has not been observed in other species. Finally, a third
a portion of the signal peptide. Utilization of exon 1 or 2 isoform (class C) has been detected in humans that arises
seems dependent on two different promoters regulated in a from an internal splice site within exon 5, which joins 49
tissue-specific manner (Adamo et al. 1993; Lund 1998). nucleotides of exon 5 with exon 6. This insertion, like in ro-
Exons 3 and 4 are invariant, and encode the remaining por- dent class B, causes a frame shift and premature termination
tion of the signal peptide, the mature IGF-I peptide, and a in exon 6. Alignment of the E peptide sequences of the 3
portion of the E peptide. The rest of the E peptide is en- human classes and the 2 rodent classes of IGF-I (Fig. 2) in-
coded by exons 5 and (or) 6. Most IGF-I transcripts skip dicates the unique human isoform is defined as IGF-IB, and
exon 5 and splice exon 4 directly to exon 6, and are defined the human isoform most similar to class B IGF-I in other
as class A. The inclusion of exon 5, which is 52 nucleotides vertebrates is termed IGF-IC.
in length, causes a frame shift in the open reading frame of
the subsequent exon and gives rise to a premature stop co- IGF-I processing
don within exon 6. This splice form, class B, only occurs in
up to 10% of the igf1 transcripts. The class A and B E pep- Peptide cleavage
tides share only 50% sequence homology at the amino acid Once translated, IGF-I prepropeptides require multiple
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Fig. 2. Sequence comparisons of IGF-I E peptides. The EA peptides from human and rodents are encoded by exons 4 and 6, and include 2
putative N-glycosylation sites (shown in bold). The human EB peptide is encoded by exons 4 and 5 and does not have a known comparable
peptide in rodents. The IBE1 and IBE2 peptides are produced by protease cleavage sites (boxed residues). IBE1 has been shown to have
mitogenic activity (Siegfried et al. 1992). The human EC peptide is most similar to the rodent EB peptide. Inclusion of exon 5 causes a
frame shift and premature stop codon in exon 6. One putative protease cleavage site exists (boxed residues). The peptide used for MGF
studies in vitro is underlined (Yang and Goldspink 2002).

processing steps prior to producing a mature IGF-I peptide. codon still gets secreted from 293 cells (Duguay et al.
All isoforms give rise to an identical 70 amino acid protein 1997).
containing the same B-, C-, A-, and D- domains, named for
their homology to insulin. Post-translational processing has Glycosylation of E peptides
been examined in both 293 and Chinese hamster ovary cell The IGF-IA E peptides contains two potential N-glycosy-
lines (Duguay 1999). The processing seems to occur via a lation sites at Asn92 and Asn100 (Fig. 2, shown in bold).
constitutive secretory pathway, similarly directed by class 1 Owing to the frame shift caused by the insertion of exon 5,
and 2 signal peptides (Tan et al. 2002). The peptide precur- both sites are nonexistent in IGF-IB. Glycosylation of both
sor (proIGF-I) contains the E peptide in addition to the do- sites has been detected in vitro (Bach et al. 1990; Wilson et
mains in the mature peptide. A pentabasic motif near the al. 2001). Glycosylation has been shown to be a critical step
end of the D domain (Lys65–X–X–Lys68–X–X–Arg71–X– in producing a fully functional protein, such as the insulin
X–Arg74–X–X–Arg77) contains 2 putative cleavage sites, receptor (Ronnett et al. 1984) and fibroblast growth factor-6
Arg71, and Arg77 (Duguay et al. 1995). This motif is in- (Ronnett et al. 1984), but its significance to IGF-I function
cluded in all classes of IGF-I. It is most likely that Arg71 is has yet to be determined.
involved in cleavage, as the 76 amino acid long peptide re- As summarized above, the expression and processing of
sulting from cleavage at Arg77 has only been observed in the gene encoding IGF-I has been well characterized in vi-
cell culture overexpression studies. For Arg71 to occur, tro. It is generally accepted that the mature IGF-I peptide is
Lys68 must be present, which has been shown in mutational the main mediator of IGF-I actions via the IGF-IR, and the
analysis of this region (Duguay et al. 1995). Cleavage at fact that IGF-I can drive cell proliferation and differentiation
Arg71 is mediated by serine proteases from the subtilisin- in multiple cell types and tissues has been repeatedly dem-
related proprotein convertase family (SPC) (Duguay et al. onstrated. However, it has not been confirmed that this is
1997). SPCs are expressed in many tissues, and have also the only activity associated with the entire IGF-I propeptide.
been shown to cleave precursors of the insulin receptor and It remains to be determined whether IGF-I-mediated effects
nerve growth factor. Because SPCs are located in the se- are due, in part, to the presence of a particular E peptide, or
cretory pathway of the cell, cleavage of the E peptide is whether there are completely novel cellular responses to E
likely to occur intracellularly. The final removal of Arg71 peptide expression. Ultimately one needs to ask ‘‘Why
is possibly accomplished by a carboxypeptidase. splice?’’.
Although efficient cleavage of the E peptide has been
shown to occur using furin and other SPCs in culture, not
all E peptides seem to be cleaved prior to IGF-I secretion. Potential functions of IGF-I E peptides
Several reports in the literature have detected the secretion The first indication that E-peptides might possess bioac-
of proIGF-IA from human fibroblasts and other cells, but tivity occurred more than a decade ago (Siegfried et al.
not human IGF-IB (Conover et al. 1993; Wilson et al. 1992). The predicted amino acid sequence of human IGF-
2001). Whether cleavage of EA peptide occurs extracellu- IB suggested that there were multiple sites that could
larly or whether proIGF-IA possesses bioactivity has not undergo proteolytic cleavage and produce 2 peptides in ad-
been determined. However, it has been shown that the E dition to IGF-I protein, termed IBE1 and IBE2. The poten-
peptide is not required for secretion of IGF-I. Expression of tial cleavage sites and the resultant peptides are indicated in
a mutant IGF-I propeptide with Arg71 replaced by a stop Fig. 2. These peptides could not be produced by IGF-IA or
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794 Appl. Physiol. Nutr. Metab. Vol. 31, 2006

IGF-IC, nor were there any homologous proteins found in human IGF-IB homolog has not been detected in other spe-
known sequence databases. Exposure of cells to a synthetic cies. Splicing from within exon 5 to exon 6 occurred imme-
analog of IBE1, but not IBE2, resulted in a concentration- diately after the sequence encoding the putative cleavage
dependent stimulation of cell growth. Further studies dem- site, which could produce the IBE1 peptide. Therefore, the
onstrated that the specific binding activity of the peptide in IBE1 peptide was missing from the human IGF-IC, and, by
cells was not affected by the presence of insulin or IGF-I, extension, from rodent IGF-IB, which would eliminate the
nor was activity prevented by presence of a neutralizing mitogenic properties of this peptide. The speculation was
antibody to the IGF-I receptor. Thus, one fragment of hu- that the alternative splicing mechanism found in IGF-IC
man IGF-IB E peptide possessed growth-promoting activity was one way a cell could reduce proliferative effects poten-
independent of IGF-I. This study was the first to demon- tially caused by IBE1 production.
strate that, similar to other prohormones such as progluca- This scheme was challenged by the studies reported by
gon (Bell et al. 1983), IGF-I could contain multiple the Goldspink laboratory (reviewed in Goldspink 1999). Ex-
bioactive peptides. Later, a second group generated trans- pression of IGF-I splice forms was monitored in rabbit
genic mice that expressed human IGF-IB under a cardiac muscles subjected to stretch, where it was found that exon
muscle specific promoter (Reiss et al. 1996). As would be 5 inclusive transcripts increased. They called this transcript
expected, the hearts in the transgenic mice exhibited ram- mechano growth factor (MGF) to indicate the increased ex-
pant myocyte proliferation leading to cardiomegaly. pression of this isoform in response to stretch or damage.
Although this is consistent with the previous study, one can- Sequence analysis shows that MGF is equivalent to human
not separate the effects of IGF-I per se on the heart from IGF-IC and rodent IGF-IB, and although it was treated as a
those of the E peptide. Further, there is not a published muscle-specific isoform, it was present in other tissues, in-
study with human IGF-IA expressed exclusively in the mur- cluding liver (Chew et al. 1995). The ability to express
ine heart to determine if the proliferation effect is isoform MGF in response to damage or overload diminished with
specific. However, high expression of human IGF-IA in age in skeletal muscle from both humans and rats (Hameed
mouse skeletal muscle does cause a significant elevation in et al. 2003; Owino et al. 2001), suggesting that the aging-re-
circulating IGF-I and leads to cardiac pathology (Delaughter lated loss in the ability to repair after damage might be
et al. 1999). This shows that IGF-I itself could have pro- based on the ability to express a specific isoform of IGF-I.
duced the effects observed in the human IGF-IB transgenic
animal independent of any actions of IBE1. Similar to the original observations of IBE1 (Siegfried et
al. 1992), transfection of MGF into C2C12 cells increases
Studies of the processing and the activity of IGF-I have cell proliferation, as does exposure of these cells to a syn-
shown that IGF-I mediates its effects predominantly via the thesized fragment of the E peptide from MGF (shown in
IGF-I receptor (IGF-IR). Ligand binding stimulates the in- Fig. 2; Yang and Goldspink 2002). The choice of this partic-
herent tyrosine kinase activity of the receptor, which, in ular fragment was somewhat mysterious. The peptide
turn, initiates multiple signaling processes and leads to spanned from the exon 4–5 junction within the E peptide to
changes in gene expression and protein synthesis. To bind the termination in exon 6, but did not include the entire E
to this receptor, IGF-I must be outside of the cell, and there- peptide identified in the liver (Chew et al. 1995). Further, if
fore either secreted from the same tissue bed or transported the predicted cleavage sites that produce IBE1 and IBE2 are
via the circulation and resident in the extracellular matrix. active (Siegfried et al. 1992), two peptides would result that
The studies mentioned above have shown that both the ma-
have no significant sequence homology to IBE1 or IBE2.
ture IGF-I protein and proIGF-IA are secreted into the ex-
Culture conditions for C2C12 cells may not possess the ap-
tracellular space. A recent study has provided evidence that
propriate proteases to release these peptides, and so it has
human proIGF-IB might traffic differently. Tan et al. (2002)
not been clearly established which of these 3 possible pepti-
constructed chimeric IGF-I precursors inserting green fluo-
des are responsible for the increased proliferation measured
rescent protein (GFP) between the signal and mature peptide
in the treated cells.
domains, and examined where the products went in cultured
HeLa cells. When the chimeras contained exon 5 and not
exon 6, GFP fluorescence was concentrated in the nucleolus. Can E peptides benefit skeletal muscle?
Furthermore, the EB peptide was not cleaved, which sug-
gests that proIGF-IB might be an active intracellular form The timing of MGF expression in concert with damage
of IGF-I. The EB peptide contains a known nucleolar local- combined with the potential mitogenic properties of this iso-
ization motif (Weber et al. 2000) that is not present in the form set the stage for an IGF-I that could be the key to en-
EA peptide. This is not the first instance of nucleolar local- hancing repair of muscle. Muscle damage instigates the
ization of a growth factor (Pederson 1998). For example, fi- activation of satellite cells, leading to proliferation and dif-
broblast growth factor-3 (FGF-3) is found in the nucleolus ferentiation of this cell population, which then can replace
and is also secreted, and these changes in the distribution of destroyed regions of the fibers with fresh myonuclei. The
FGF-3 can inhibit or promote cell growth (Kiefer and Dick- presence of MGF could increase satellite cell proliferation,
son 1995). It is possible that the two isoforms of IGF-I are thereby providing more cells for repair. The Goldspink lab
involved in a similar competition in promoting cell prolifer- has proposed that MGF may be the optimum therapeutic
ation or differentiation. agent for muscle growth and repair. Plasmid delivery of this
Later identification of the existence of human IGF-IC iso- isoform into rabbit skeletal muscle promotes increased
form in liver tissue helped to address the conundrum of di- muscle mass within 2 weeks of injection (Goldspink 2005).
vergent isoforms in humans and rodents, even though the Such a rapid response suggests that the potency of MGF
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Barton 795

delayed as a result of the need to complement the single-stranded viral DNA prior to expression. However, IGF-I expression is sustained for the lifetime of the infected myonucleus and
Fig. 3. Mode of IGF-I delivery can affect mechanism of muscle hypertrophy. Satellite cells are activated at the onset of damage, and undergo proliferation and differentiation prior to
fusing to damaged areas of fibers. To a lesser extent they are also activated during the process of normal growth and are either incorporated into existing fibers or fused to create new
might exceed that of IGF-IA, although the duration of these

fibers. Plasmid delivery of the igf1 gene instigates the damage process, which is simultaneous to IGF-I production, thus enhancing the proliferation and (or) differentiation of satellite
cells. This method can also help to enhance normal growth, but only while IGF-I production remains high. AAV delivery also instigates the damage process, but IGF-I production is
effects have not been reported.
Even if this were true, increased expression of IGF-IA can
enhance the muscle repair process in aging transgenic mice
such that it is indistinguishable from repair in young animals
and maintains mass and strength while age-matched control
muscles succumb to sarcopenia (Barton-Davis et al. 1998;
Musaro et al. 2001). So is increased MGF expression simply
a way to increase IGF-I availability at the site of damage, or
does the E peptide of this isoform have unique bioactivity?
This question remains unanswered because competing labs
have used different methods of increasing the expression of
IGF-I isoforms.
To provide a more even playing field, we have recently
performed a direct comparison of rodent IGF-I isoform ef-
fects in skeletal muscle (Barton 2006). Using viral-mediated
transfer of murine IGF-IA and IGF-IB (also known as
MGF), we determined the expression and production of
IGF-I in young and mature animals, and assessed the func-
tional benefits of increased IGF-I to skeletal muscles. Young
animals provided skeletal muscle with activated satellite
cells during the rapid growth phase, whereas mature animals
were beyond active growth, such that the pool of satellite
was predominantly quiescent. In young animals, both iso-
forms promoted equivalent hypertrophy, which was ob-
served 2 months after viral injection. In mature animals,
only increased expression of IGF-IA resulted in hypertro-
phy, even though both isoforms had increased production of
IGF-I protein.
In contrast to previous reports, MGF is certainly not more
potent than IGF-IA, the dominant isoform, in increasing
muscle mass. However, this study provides insight into the
mechanisms underlying IGF-I isoform actions. The fact that
can provide long-term enhancement of satellite cell activation during normal growth.

there was no response in mature muscle suggests that acti-

vated satellite cells need to be present for MGF activity.
This is consistent with the results after plasmid delivery of
MGF, for the process of injection instigates damage and ac-
tivates satellite cells. Why, then, was hypertrophy after viral
delivery observed 2 months after injection and not before,
whereas plasmid delivery of MGF into skeletal muscle pro-
duced significant hypertrophy within weeks of injection?
This, too, points to the need for expression of IGF-IB/MGF
in concert with activated satellite cells. The comparisons of
these two methodological approaches are schematized in
Fig. 3. First, plasmid delivery, when used without agents en-
hancing DNA uptake, provides rapid although inefficient
and transient transgene expression (Wolff and Budker
2005). Expression overlaps with the activation of satellite
cells owing to damage, and can help to expand the satellite
cell population for driving rapid hypertrophy. However, de-
cay of expression over time suggests that hypertrophy might
also fade with time, specifically as myonuclei harboring the
injected DNA are replaced by nascent myonuclei. Therefore,
repeated delivery of plasmids would be necessary to main-
tain the effect. In contrast, viral transgene expression may
not occur simultaneously with the damage inevitably caused
by the injection itself because the single-stranded genome of
adeno-associated virus (AAV) requires complementation by
the host cell prior to expression. Regeneration would have
progressed further, such that activated satellite cells were
beyond proliferation and undergoing differentiation or fiber
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796 Appl. Physiol. Nutr. Metab. Vol. 31, 2006

formation. Therefore, IGF-IB/MGF expressed after viral de- pression of insulin-like growth factor I stimulates muscle cell
livery misses the activated satellite cell window, and sus- differentiation and myofiber hypertrophy in transgenic mice. J.
tained expression of IGF-IB does not lead to the same Biol. Chem. 270: 12109–12116. PMID:7744859.
dramatic increase in mass. Conover, C.A., Baker, B.K., Bale, L.K., Clarkson, J.T., Liu, F., and
Hintz, R.L. 1993. Human hepatoma cells synthesize and secrete
What are the implications for muscle-enhancing therapies
insulin-like growth factor Ia prohormone under growth hormone
based on increased IGF-I? In undamaged growing muscle,
control. Regul. Pept. 48: 1–8. doi:10.1016/0167-0115(93)90330-
the isoforms appear to have equivalent potency. Without B. PMID:8265808.
growth or damage, IGF-IA is more effective. However, Coolican, S.A., Samuel, D.S., Ewton, D.Z., McWade, F.J., and
when damage occurs, perhaps a transient boost of IGF-IB is Florini, J.R. 1997. The mitogenic and myogenic actions of insu-
exactly what is necessary to push the repair process effi- lin-like growth factors utilize distinct signaling pathways. J.
ciently. In sarcopenia, the question remains whether IGF-IB Biol. Chem. 272: 6653–6662. PMID:9045696.
could outperform IGF-IA. The answer depends upon what Delaughter, M.C., Taffet, G.E., Fiorotto, M.L., Entman, M.L., and
the actual target for IGF-IB is, and if it exists in aging Schwartz, R.J. 1999. Local insulin-like growth factor I expres-
muscle. If the target is an activated satellite cell, then it is sion induces physiologic, then pathologic, cardiac hypertrophy
not likely that this isoform would counter the muscle loss in transgenic mice. FASEB J. 13: 1923–1929. PMID:10544175.
that accompanies aging. However, in other contexts, IGF-IB Duguay, S.J. 1999. Post-translational processing of insulin-like
might be a better isoform to use. For example, the propor- growth factors. Horm. Metab. Res. 31: 43–49. PMID:10226780.
tion of active satellite cells increases with resistance train- Duguay, S.J., Lai-Zhang, J., and Steiner, D.F. 1995. Mutational
ing, and so IGF-IB might more beneficial to athletes for analysis of the insulin-like growth factor I prohormone proces-
boosting the effects of training. These potential uses and sing site. J. Biol. Chem. 270: 17566–17574. PMID:7615562.
(or) abuses still remain in the confines of the laboratory, Duguay, S.J., Milewski, W.M., Young, B.D., Nakayama, K., and
but the bridge to IGF-I-mediated therapies will be crossed Steiner, D.F. 1997. Processing of wild-type and mutant proinsu-
in the not-too-distant future. In the meantime, we will hope- lin-like growth factor-IA by subtilisin-related proprotein conver-
fully continue to successfully spell out the functional differ- tases. J. Biol. Chem. 272: 6663–6670. PMID:9045697.
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1993. IGFs and muscle differentiation. Adv. Exp. Med. Biol.
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