Available online at www.sciencedirect.

com

Growth factors, muscle function and doping

Geoffrey Goldspink1, Barbara Wessner2 and Norbert Bachl2
Recently much interest has been shown in developing a
treatment of muscle wasting associated with a range of
diseases as well as in ageing, which are major medical and
socioecomonic problems. Emerging molecular techniques
have made it possible to gain a better understanding of the
growth factor genes involved and how they are activated by
physical activity including the IGF-I gene that can be spliced to
give rise to different isoforms, one of which is called MGF that
activates muscle progenitor cells that provide the extra nuclei
required for muscle hypertrophy, repair and maintenance. This
fact that MGF kick starts the hypertrophy process clearly has
potential for abuse and has already attracted the attention of
body builders.
Addresses
1
Departments of Surgery, Anatomy and Developmental Biology, Royal
Free and University College Medical School, University of London,
Rowland Hill Street, London NW3 2PF, UK
2
Department of Sports and Exercise Physiology, Centre for Sports
Sciences and University Sports, University of Vienna, Auf der Schmelz 6,
A-1150 Vienna, Austria
Corresponding author: Goldspink, Geoffrey
( g.goldspink@medsch.ucl.ac.uk)

Current Opinion in Pharmacology 2008, 8:352357

This review comes from a themed issue on
Musculoskeletal
Edited by Martin Hohenegger
Available online 19th March 2008
1471-4892/$ see front matter
# 2008 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coph.2008.02.002

Introduction
With techniques in molecular and cell biology and the
considerable recent intensive interest shown by the big
pharmaceutical companies in developing a treatment for
muscle cachexia in a range of diseases and age-related
muscle wasting, the potential for increasing muscle mass
and strength has attracted considerable interest. While
the treatment of such conditions as muscular dystrophy or
the prevention of sarcopenia is laudable, the same therapeutic methods of increasing muscle strength and endurance will also inevitably be used by athletes. Attempts at
keeping events such as the International Olympic Games
clean are being thwarted by the increased availability of
performance enhancing agents such as growth factors, and
the admission by athletes who were Gold Medal winners
and World Champions undermines the whole concept of
open and fair competition. However, it has to be pointed
Current Opinion in Pharmacology 2008, 8:352357

out that those methods are not only used at the level of
competitive athletes on the highest sports level, but also
by an increasing percentage of leisure time sportsmen
purchasing drugs from the black market. In addition, it
can be speculated that different methodologies for gene
transfer to enhance the biological activity of growth
factors may be misused in order to increase endurance
capacity and/or muscle mass and thus strength in different
disciplines. Therefore, it is necessary to increase the
knowledge about the mode of action of muscular growth
factors concerning muscle growth regulation and thus
developing methodologies to counteract their misuse
during training and sports competitions.
There are now good medical indications for treating
muscle loss in a range of conditions, and it is realised
that loss of muscle not only results in the inability to
perform simple physical tasks but also is important for
quality of life and meeting the costs of care for an ageing
population. It is also appreciated that the musculature is a
dynamic metabolic store and in traumatic situations as it is
the source of essential amino acids and those needed for
acid base balance. Life expectancy is expected to continue to increase, and the socioeconomic costs will be
unsustainable unless commensurate increases in health
care are achieved. Increasing muscle mass and strength
therefore has to be a priority as keeping the elderly active
makes socioeconomic sense as daily exercise helps to
maintain body functions, reduces the need for daily
assistance and improves quality of life. Devising treatment for muscle cachexia that is associated with a range of
diseases such as HIV, cancer and renal disease and agerelated muscle loss (sarcopenia) considerably increases
the chances of survival, and a generic method of treating
muscle loss is a target worth billions of dollars to the
pharmaceutical industry.
Blocking negative muscle growth regulation

Just after birth the musculature in mammals increases at a

considerable rate. In the laboratory mouse it doubles
every four days [1], and similar rates occur in meatproducing animals that have been bred to increase the
duration of this rapid growth period. In humans, if one
takes into account the difference in metabolic rate, these
phenomenal rates of muscle growth are also achieved
within the first year of life. After this rapid growth period
the rate of growth is then down rated, and it is presumed
that there are negative factors as well as the lack
of positive stimulation involved. Furthermore, the
maintenance of functional muscle proteins is achieved
by balancing protein synthesis and protein breakdown,
and the possibility exists that protein turnover can be
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Growth factors, muscle function and doping Goldspink, Wessner and Bachl 353

manipulated to produce increased muscle mass and

strength.
Myostatin

In recent years a negative muscle regulatory factor named

myostatin has been discovered, which, as its name
implies, reduces muscle growth. Knocking this out at
the protein or gene level apparently offered the possibility of increasing muscle mass and strength. The myostatin gene, when mutated, is responsible for double
muscling in certain breeds of cattle, such as the Belgian
Blue, which exhibit very considerable muscle hypertrophy [2] and also in a few human subjects in which the
gene is mutated [3]. However, McMahon et al. [4]
reported that in the myostatin knockout mouse the lack
of myostatin did not ameliorate disuse atrophy. Post-natal
inactivation of the myostatin gene by targeting resulted in
a myostatin null mouse, which had an increased number
of active satellite cells [5,6] helping to explain the
increase in muscle mass. A recent paper [7], however,
showed that in these mice the increase in muscle mass
only slightly increased muscle strength. Other studies
indicated that this was probably due to an accumulation of
non-functional protein and explains the decreased muscle
specific contractile force production and a decreased
oxidative capacity of the muscles as well as impaired
respiratory and cardiovascular function [8]. This and
the finding that the use of anti-myostatin strategies result
in increased mass without a commensurate increase in
strength would handicap and not help elderly and disabled individuals.
Reduction of protein breakdown

The size of tissues in the body is determined mainly by a

balance between the rate at which proteins are synthesised and the rate they are broken down. Every few days
approximately half the enzyme molecules within our
body will break down and will be replaced. The turnover
of the contractile proteins of muscle such as actin and
myosin takes a little longer with about half of them being
replaced every two weeks or so. Animal studies have
shown that in young rats, which are producing new
muscle, protein synthesis exceeds protein breakdown,
but breakdown is, nevertheless, even higher in older
animals. This higher turnover of muscle protein is part
of the tissue adaptation that is taking place during early
post-natal growth and development [9]. Using non-radioactive isotope methods it was found that as we get older
our muscle proteins are degraded and rebuilt at less
frequent intervals, but still the process is very dynamic.
Protein degradation requires energy as does the synthesis
of muscle proteins, and it appears that the balance is more
towards decreased protein synthesis except in some disease states, for example, endotoxin poisoning, in which
muscle protein breakdown can be very rapid at all ages.
Proposals [10,11] for increasing muscle mass during ageing by slowing down the degradation process during
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healthy ageing would therefore seem to be physiologically undesirable as continual replacement of proteins is
particularly important in a mechanical tissue as this is the
way of ensuring there is no build up of non-functional
proteins and a reduction in specific strength.
Increasing positive muscle growth regulation
Androgens and treating the somatopause

Post-natal growth of muscle is very much influenced by

hormones that include protein growth factors and androgens, the circulating levels of which decrease with age.
This decrease in hormone levels in the elderly has sometimes been referred to as the somatopause as it occurs in
both males and females. Supplementing the levels of
these hormones has been found to be beneficial, for
example, oestrogen/progesterone replacement therapy
in women and administration of testosterone and of
growth hormones in some elderly men to improve muscle
strength. Males develop more muscles than females, and
one of the common types of doping for power events is
the use of synthetic steroids based on testosterone and
more recently small molecules called SARMS that
enhance the action of the testosterone receptor. As
well-improved methods of detection of synthetic steroids
are available there is now a growing awareness of their
carcinogenic properties and the possibility of inducing
prostate cancer. Also the mascularising effects may be
unwelcome by younger females or even elderly ladies
receiving treatment for sarcopenia.
The growth hormone/insulin-like growth factor (GH/IGF-I)
axis

The liver is the main source of circulating IGF-I, and GH

up regulates not only the synthesis of IGF-I, but also IGF
binding proteins. However, it became clear that if the
liver IGF-I gene was deleted [12,13] expression of the
IGF-I gene occurred in other non-hepatic tissues, and
individual organ weights showed no marked difference
even though circulating levels of IGF-I were decreased.
This emphasises the importance of the direct effect of
GH in the local upregulating of the IGF-I gene and
production of autocrine/paracrine IGF-I production for
growth of organs, including skeletal muscle. The levels of
GH and IGF-I reach their peak levels during adolescence. With increasing age, however, there is a marked
decline in the circulating levels of GH and a somewhat
smaller decline in circulating IGF-I [14]. In young adults
who are GH deficient, the administration of recombinant
human GH (rhGH) has positive effects on muscle mass
and function [15]. Treatment of GH-deficient adults for
an extended period of time results not only in increased
muscle strength but also in decreased body fat [16].
These findings have led to the belief that older individuals with decreased levels of circulating GH and IGF-I
can benefit from GH therapy and have encouraged the
illicit use of GH among athletes, even those competing in
secondary school level, in an attempt to enhance perCurrent Opinion in Pharmacology 2008, 8:352357

354 Musculoskeletal

formance. Furthermore, a recent study on transgenic mice

in which the IGF-I receptor has been knocked out shows
that these animals are still able to undergo muscle hypertrophy, which strongly suggests that IGF-IEa is not the
main initiator of muscle growth [17].
IGF-I gene splicing and the unique C-terminal peptide of
MGF

The IGF-I gene, like many genes, can be spliced to

produce several RNA transcripts from which different
pro-peptides are derived, one of which is expressed in
response to mechanical signals [1820] (Figure 1).
Human skeletal muscle has been found to express at
least three isoforms [21]. These are IGF-IEa, which is the
liver type or systemic form, IGF-I Eb of which nothing is
known about its function and IGF-I Ec, an autocrine/
paracrine form, which is particularly interesting as it is
expressed in response to mechanical stimuli and cellular
damage. Because of confusion in the nomenclature, the
latter splice variant was called mechano growth factor
(MGF), as this is IGF-I Eb in the rat and IGF-I Ec in the
human. As well as having a different carboxy peptide
sequence, MGF expression kinetics are different to those
of IGF-IEa. Haddad and Adams [22] found that MGF
expression peaks earlier than that of total IGF-I mRNA.
Hill and Goldspink [23] showed that following muscle

damage MGF is produced as a pulse lasting only two days

or so, followed by longer lasting expression of IGF-IEa
mRNA. This expression pattern is consistent in accord
with our in vitro data [24,25], which shows a role for
MGF in activating muscle satellite (progenitor) cell proliferation but preventing them entering the myogenic
pathway (Figure 2). These mononucleated muscle stem
cells are usually positioned just beneath the basal lamina
but outside the membrane of the muscle fibre. They were
first described by Mauro [26] as satellite cells because of
their location with respect to the muscle fibres. It was
then realized that in muscle that is a post-mitotic tissue,
these cells provide the extra nuclei for post-natal growth
[27] and repair following local injury of muscle fibres.
Recent work by Ates et al. [25] using defined muscle
stem (progenitor) cells from human muscle biopsies confirmed initial experiments in mouse muscle-line cultures
[26]. These findings are in accord with the work published by Butler-Brownes group [28] showing that
although IGF-I does not initiate the replication of satellite cells, it causes them to enter the myogenic pathway
and to fuse to form myotubes or adult muscle. Also
Grounds group [29] showed that IGF-I was not involved
in the very early stages of repair. Our latest in vitro work
[25] using human stem muscle cells is encouraging as it
seems that even in conditions such as muscular dystrophy

Figure 1

Splicing of the IGF-I gene. The IGF-I gene contains six exons. Both exons one and two contain transcription start sites and thus the primary transcript
may contain either Class 1 or Class 2, and it is believed that the transcription is initiated differently in different tissues. In response to mechanical stress
the IGF-I gene is first spliced towards the MGF IGF-IEc (in the human) and then later to IGF-IEa, which is same as the liver IGF-I and the main source of
anabolic agent. The peptide products from exons 1 and 2 and the MGF E domain peptide are cleaved off from the transcript of exons 3 and 4, which
become mature IGF-I protein. The latter binds to the IGF-I receptor and is apparently the same as in all the IGF-I splice variants. However, the MGF E
peptide of MGF is unique because of reading frame shift, which occurs during splicing and has been shown to have biological activity in expanding the
muscle progenitor (stem) cell pool in vitro and in vivo that is not mediated by IGF-I receptor.
Current Opinion in Pharmacology 2008, 8:352357

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Growth factors, muscle function and doping Goldspink, Wessner and Bachl 355

Figure 2

Lineage transitions of muscle stem cells. This diagram indicates the role of MGF (human IGF-IEc) E peptide in relation to its initial activation of the
mononucleated pluripotent stem cells in order to expand the pool of muscle progenitor (stem) cells. Also shown is the second phase that is induced by
IGF-I leading to the myoblasts becoming committed to the myogenic pathway and fusion with myotubes or mature muscle fibres undergoing repair or
adaptation. Information about NOTCH and WINT expression is taken from Conboy and Rando [39].

and ALS as well as normal muscle it may not be necessary

to transplant stems cells if the progenitor cell pool can be
replenished by administration of MGF provided either as
the peptide or by gene therapy.
MGF as a therapeutic agent for treating muscle wasting
conditions

This rationale is based on the finding that older human

subjects produce less MGF than younger individuals [30].
In animal experiments MGF was also considerably lower in
older animals even when mechanically challenged to the
same or greater extent [31], and it is also known that ageing
muscle takes longer to repair [32]. Also muscles of the
dystrophic mdx mouse are unable to produce this growth
factor in response when physically challenged [33]. Interestingly, this ability was restored by autologous mesochymal stem cell therapy in which the dystrophin gene has
been corrected [34]. Primary cultures taken from patients
with adult muscular dystrophies and ALS patients [25]
have markedly lower yields of muscle progenitor (stem)
cells. Therefore, expanding the muscle stem cell pool using
MGF or just its E peptide offers considerable potential as a
generic approach for increasing the specific strength of
muscles in many conditions that are accompanied by
muscle cachexia as well as age-related muscle loss.
Individuals enter this vicious cycle as they exercise less
and less, particularly as they get older and their muscles
become stiffer and stiffer, in which lack of exercise results
in loss of muscle, which in turn usually results in even less
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exercise. It would seem therefore that a rational way to

break this cycle would be to administer MGF and
possibly just the E peptide or an iRNA that induces
the splicing towards MGF. Studies have been carried
out using IGF-IEa and MGF cDNA in viral vectors, and
although some improvement in muscle mass was reported
[35] a long period of time was needed representing about
one-third of the life of the mouse. There are risks associated with this approach as even engineered viruses have
been found to evoke an immune response. The London
group has recently used a gene therapy approach by
inserting the MGF and IGF-IEa coding sequences in a
non-viral vector. This resulted in an increase in muscle
strength of 34% within three weeks after intramuscular
injection into the anterior tibialis muscle of young mdx
mice [36]. There seems to be little doubt that it is
extremely effective although gene therapy may not be
the method of choice. For the treatment of otherwise
healthy elderly people other approaches are being investigated. The administration of MGF using the C terminal
peptide or E peptide is being explored. Problems are
encountered as its mRNA is designed to be expressed as a
pulse lasting a day or so, and its peptide is also broken
down within this same time scale. Use of the latter as a
therapeutic agent requires the peptide to be stabilised,
and several standard methods have proven to be successful including amino acid and L to D substitutions as well
as protection of the N and C termini. Delivery using
miniosmotic pumps has also proven to be very successful
in mice that have received a major cardiac infarct [37]. As
Current Opinion in Pharmacology 2008, 8:352357

356 Musculoskeletal

this work is now in the public domain the prospects exist

for markedly improving muscle strength in cachectic
conditions as well as treating people who have suffered
a myocardial infarction [38] or using its neuroprotective
properties as an emergency treatment for stroke.

Conclusion
Our improved understanding of the local control of muscle
mass and strength offers the possibility of treating muscle
cachexia in a range of diseases particularly using MGF,
which is derived from the IGF-I gene. However, this also
presents a major problem for misuse in athletic events that
require power as it already available over the Internet.

Acknowledgements
Dr Goldspink was a visiting professor at the University of Vienna. Previous
funding for the MGF work was from the Wellcome Trust, WADA, and a
European Frame Work 5 PENAM Grant.

References and recommended reading

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