This staff working paper was discussed at the Council's
March 2003 meeting.
It was prepared by staff solely to aid discussion, and does not represent
the official views of the Council or of the United States Government.|
Our muscles are essential to human life in a variety of ways. They
are central components of physical strength and speed, attributes
that are admired and celebrated in most human cultures. Our mobility
depends on muscles, whether we use them to walk, or when we just
use them to turn the wheel of a car or put our foot down on the
accelerator or the brake. As a basic component of physical vigor
they also play a role in human attractiveness. As such, muscle tone
is a major contributor to the “sense of self” developed
by each person. Although there are several different types of muscles
in the human body, we will concentrate here on processes affecting
The strength and fitness of healthy muscles are largely a function
of their exercise. In our youth, active use of our muscles in play
and in sports strengthens and develops them. At puberty, production
of estrogen and testosterone enhances these processes, so that the
peak of human muscular development is usually between 20 and 30
years of age. Except for people whose daily work requires much physical
exertion, maintaining peak muscular strength and endurance later
in life requires regular exercise and fitness training. Some pursue
this avidly, while others do not.
The strength and size of human muscles declines by about one-third
between the ages of 30 and 80.2 Diminished capacity or loss of a
previous ability to do a physical task is a common experience during
human aging. The age-related loss of muscle size and strength has
been named “sarcopenia”.3 In addition, there are a variety
of diseases of muscle tissue (muscular dystrophies), many caused
by specific genetic mutations.
We have an increased understanding of how many of the important
genes in muscle cells function and are regulated.4 The parallel
development of gene therapy techniques for efficient and controlled
expression of genes is beginning to open up new possibilities for
treating muscular dystrophies as well as maintaining “youthful”
muscle size and strength
during the aging process. It is thus timely to begin discussions
of the ends to which such increased understanding and power to modify
should be put when it comes to human muscles.
As discussed in more detail below, biotechnological approaches
to repair and strengthening of diseased and aging skeletal muscles
have been demonstrated in experimental animals. The application
of these approaches (once they are shown to be safe and effective)
to treat human muscular dystrophies clearly falls within current
understandings of appropriate therapy. A more difficult judgment
is whether we should
extend the application of these approaches to a variety of other
situations that are currently “beyond therapy”.
Muscles do not generate human strength and speed in isolation.
Muscles need to be physically integrated with, and function harmoniously
through their attachments to nerves, tendons, ligaments, and bones.
While the focus in this paper is on the activity of muscle cells,
we should remain alert to the possibility that biotechnological
approaches that strengthen only muscles may lead to imbalances in
the interactions with other components of the body, and subsequent
Muscles in idealizations of male human form
Muscles play a prominent role in idealizations of male human form.
A classical picture of excellence of the youthful male human form
is Michelangelo’s sculpture of David, completed around 1504
(see Figure 1). Here the muscles are depicted as well-
Figure 1. Michelangelo's David
(ca. 1504) i
Figure 2. Arnold Schwarzenegger (ca. 1980)
proportioned but without much articulation of individual muscles.
The strength and
power of David’s skeletal muscles shine through the marble,
and leave us with a mental picture of the classical ideal of muscular
development and proportion.
A more contemporary idealization of the male human form is the
picture of the modern male body-building champion and actor, Arnold
Schwarzenegger (Figure 2). Through specialized weight training and
alleged use of anabolic steroids, his muscles (particularly the
biceps) have become much larger than those pictured in the statue
of David, and the different groups of skeletal muscles are individually
Although different in proportion and muscle articulation, both
the classical and contemporary pictures testify to the importance
of muscles in images of male strength and power. Large muscles were
also supposed to help males attract females, a point that is still
emphasized by males working out in gyms. “I am exercising
and increasing the size of my muscles so that the chicks will notice
Interestingly, female body-builders reportedly initially pursued
the same path illustrated by the picture of Arnold Schwarzenegger.
The result was female body-building champions with smaller but similarly
individually developed and articulated skeletal muscles. More recently
there has been an “aesthetic” reaction against the resulting
female muscle “overdevelopment” and, commercially at
least, the more popular and profitable activity today is women’s
Genetic treatments are not the only biotechnological approach to
increasing muscle size and strength. Anabolic steroids are among
the most widely used chemical compounds that are used in combination
with weight lifting to increase muscle size and strength. Examples
of such compounds include methandrostenolone (Dianabo 1), Boldenone
(Equip-gan), Stanazolol (Winstrol V) and Drostanolone (Masteron).
As information about their effects has diffused throughout American
society, they are coming to be used more and more by professional
and amateur athletes. Use of some of them is banned by anti-doping
organizations. Many (including the ones listed above), are listed
as available for sale on the Internet.
Cellular multiplication and differentiation in skeletal muscle
The major cell type present in skeletal muscle fibers is the multinucleated
myotube. These fibers arise from the fusion of mononucleated myoblast
cells with each other and with pre-existing myotubes. Myoblasts,
in turn, are formed by differentiation of a particular stem cell
found in muscle tissue, called a satellite cell.5
The multiplication and differentiation of satellite cells into
myoblasts is regulated by several specific protein growth factors
(primarily insulin-like growth factor 1 (IGF-1) and hepatocyte growth
factor (HGF)) and also influenced by hormones such as growth hormone,
testosterone and estrogen. Secretion of growth hormone by the pituitary
acts on the liver to stimulate synthesis and release of IGF-1, which
is released into the circulation (Figure 3). In muscle tissue, IGF-1
binds to specific receptors on the surface of satellite cells to
stimulate cell multiplication, producing more satellite cells, and
differentiation of satellite cells into myoblasts (see Figure 4).
Growth Hormone (GH) Secreted
SKELETAL MUSCLE growth stimulated
Figure 3. Hormone action and muscle growth stimulation
Importantly, a slightly different form of IGF-1 (mIGF-1) is also
produced locally in muscle tissue in response to stretching the
muscles (exercise). This form is thought to act the same way as
circulating IGF-1 does in stimulating satellite cell multiplication
and differentiation. However, because mIGF-1 is slightly different
in chemical structure from IGF-1 produced in the liver, mIGF-1 apparently
does not enter the circulation, so its effects can be restricted
to promoting growth and repair of muscle tissue locally.
It is a common human experience that muscle size and strength can
be increased by exercise. The number of muscle fibers increases
as a consequence of exercise-induced stimulation of the multiplication
and differentiation of muscle stem cells. Exercise both transiently
damages muscles and causes them to increase in size and strength.
While exercise was previously the only way to do this, biotechnological
Figure 4. Schematic diagram of some important processes
in skeletal muscle fiber growth and repair.
development have introduced new possibilities. The genes for animal
and human IGF-1 have been cloned and their DNA sequences determined.
Gene expression vectors have been developed that permit the regulated
production of IGF-1 proteins (both the liver and muscle forms) for
investigation. So IGF-1 genes can be introduced into cells and experimental
animals to determine the effect of enhanced IGF-1 (and/or mIGF-1)
production on muscle size and strength.
Loss of muscle size and strength on aging: sarcopenia
With aging, we become more sedentary and use our muscles less.
With aging the production of growth hormone and circulating IGF-1
also decreases. There is thus less IGF-1 available to keep the muscles
large, and they become smaller and weaker. In addition, aged muscle
cells are apparently less responsive to the action of IGF-1 and
mIGF-1 6 so that the impact of even vigorous exercise on muscle size
and strength diminishes with age. Figure 5 graphically illustrates
the appearance of leg muscles as they become smaller and weaker
with age (sarcopenia).
As we age, several things change that predispose to the development
of sarcopenia. We either reduce the output of, and/or become more
resistant to, anabolic stimuli to muscle such as central nervous
system input, growth hormone, estrogen, testosterone, dietary protein,
physical activity and insulin action. The loss of alpha-motor neuron
input to muscle that occurs with age7 is believed to be a critical
factor8. Nerve cell-muscle cell connections are critical to maintaining
muscle mass and strength.
A loss of muscle size and strength in a significant problem for
older persons. While not painful or directly debilitating, sarcopenia is associated
with an increased tendency to fall and break bones. Such falls and
broken bones are major causes of morbidity among the elderly.
This image is from the informative
Internet site www.sarcopenia.com.
Figure 5 – Illustrating progressive age-related loss of muscle
tissue (sarcopenia) iii
Selective stimulation of skeletal muscle growth in experimental
Local injection of regulated exogenous “muscle-specific”
Recombinant viruses, engineered to express a specific foreign gene,
are frequently used to stimulate the production of functionally
effective amounts of the foreign protein to treat disease. Recombinant
viruses created from genetically engineered human
Adenovirus-associated Virus (AAV) have proved to be efficient delivery
systems of foreign genes into muscle cells. As AAV is a small virus,
only small foreign genes can be used effectively with this virus.
Fortunately, the DNA sequence encoding IGF-1 is small enough to
function well in AAV-based recombinant viruses.
In experiments described by Barton-Davis and coworkers 9, AAV recombinant
viruses containing a rat IGF-1 gene were injected into the anterior
compartment of the rear legs of mice containing the extensor digitorum
longus (EDL) muscle. The resulting increased IGF-1 production promoted
an average increase of about 15% in EDL muscle mass and strength
in young adult mice. Strikingly, such injections led to a 27% increase
in the strength of the EDL muscles of 24-month (old) mice, thus
substantially reducing the decrease in EDL muscle size and strength
observed in untreated old mice.
In this study, approximately 1 x 1010 recombinant AAV particles
in 100 µliters of fluid were injected into a single small
muscle compartment of mice. If such treatments were eventually to
be applied to humans, large amounts of recombinant AAV containing
the human IGF-1 DNA sequence would be required. Assuming such future
treatments were shown to be safe and effective, producing sufficient
recombinant AAV to treat millions of dystrophic and aging humans
would remain a substantial logistical challenge. However, there
may be ways around this logistical problem involving the production
and transplantation of human muscle stem cells engineered to produce
more IGF-1 (see below).
IGF-1 transgenic mice
The ability to create transgenic mice, in which an appropriately
regulated foreign gene is expressed throughout embryonic and adult
life, offers another way to assess the biological role(s) of the
transgene product. Musaro et al10 introduced a rat mIGF-1 transgene
into early stage mouse embryos, where it became integrated with
mouse chromosomal DNA. The resulting transgenic mice produce substantial
amounts of rat mIGF-1, in addition their production of mouse IGF-1
In these transgenic mice, the rat mIGF-1 transgene was connected
to gene expression regulatory elements that restricted production
of the rat mIGF-1 protein to muscle tissues containing primarily
fast twitch fibers. Embryonic development of these transgenic mice
proceeded normally. However, as early as 10 days after birth, enlargement
of skeletal muscles where rat mIGF-1 protein was being produced
was observed in the transgenic animals compared to the non-transgenic
Moreover, the skeletal muscle enlargement persisted as the transgenic
Muscle size and strength were maximal around six months in unmodified
(wild type) mice and decreased as expected by 20 months of age.
In contrast, at 20 months the size and strength of skeletal muscle
in the rat mIGF-1 transgenic mice remained at essentially the same
as at six months.
In previous studies of this type, the IGF-1 transgene was not connected
to gene expression regulatory elements that restricted production
of mIGF-1 to muscle tissue.
This led to overproduction of IGF-1 in the circulation, and eventually
to pathological enlargement of the heart muscle. The growing understanding
of muscle physiology at the molecular level coupled with sophisticated
genetic engineering has made it possible to enlarge skeletal muscles
selectively, without damaging heart muscles in the process.
These and other experimental results stimulate thought about possible
extensions of these approaches to humans. Similar procedures might
be useful treatments for various diseases of muscle tissue, and
well as a possible use in older persons to counteract sarcopenia.
However, each of the procedures described above has technical/logistic
problems that would need to be overcome before any treatment could
be applied on a large scale.
Could these biotechnological approaches be applied
to human muscles?
Could the mIGF-1 gene procedures that increase skeletal muscle
size and strength in young and old experimental animals be adapted
for use in humans? Based on our current understanding, at least
three different approaches could be considered. First, one might
develop recombinant AAV-based virus vectors containing the human
mIGF-1 gene under the control of appropriate regulatory elements
that would limit its expression to muscle cells near the site of
injection. Alternatively, one might introduce an appropriately regulated
mIGF-1 gene into human embryos, as was done in the experiments with
mice. Finally, a combined approach might be developed in which one
first isolated human muscle stem (satellite) cells and expanded
them in vitro, next introduced an appropriately regulated human
mIGF-1 gene into those cells in vitro, and finally transplanted
the genetically modified satellite cells back into the muscles of
the person being treated.
The first approach would be similar to other human gene therapy
projects. The appropriately regulated human mIGF-1 gene would be
combined with a vector capable of efficient delivery to muscle cells,
perhaps AAV. This material could be produced in large volumes, carefully
characterized by tests in experimental animals, stored frozen and
used as needed. While the logistics of producing the large amounts
of recombinant AAV that would be required for treatment of thousands
or millions of patients are daunting, in principle this would be
possible. The advantages of this approach are 1) that it would develop
and use a single, well-characterized biological agent; 2) that treatment
could be started very slowly by introducing the recombinant mIGF-1
gene-containing AAV into one muscle at a time and evaluating its
effects; 3) that treatment could be stopped immediately if untoward
side effects developed. Disadvantages include 1) the possibility
that a large number of injections would be necessary to treat each
of the large number of human skeletal muscles; 2) the possibility
that this would not be an effective treatment for humans who had
antibodies to AAV as a consequence of a previous infection.
The second approach is a radical proposal, as it envisions treatment
of blastocyst stage human embryos in vitro with a genetic procedure
that was intended to change the early development of skeletal muscle
size and strength and reduce the rate of loss later in life. This
approach shares some advantages with the first approach in that
a single biological agent could be prepared and characterized that
could treat all embryos; 2) that only a single treatment early in
embryonic development would be needed, instead of multiple injections
into different muscles. The major disadvantages of this approach
are the difficult ethical questions it would raise.
The third approach depends upon the ability to isolate human muscle
stem (satellite) cells and expand them in vitro. The isolated human
muscle stem cells would then have their mIGF-1 production genetically
modified by introducing an appropriately regulated exogenous mIGF-1
gene copy. In theory, this could produce modified muscle stem cells
that multiplied continuously in vitro to produce larger numbers
of cells, and that differentiated appropriately in vitro. In this
case, genetically modified satellite cells would be injected into
the aging skeletal muscles. The advantages of this approach include
1) that it would develop and use a single, well-characterized biological
agent to modify the muscle stem cells in vitro and 2) the dose of
modified stem cells could be varied as necessary to optimize treatment
of individual skeletal muscles. The disadvantages include the possibility
that a separate preparation of muscle stem cells from each patient
to be treated would have to be made in order to get around the immune
Each of these approaches has advantages and disadvantages. Developing
any one of them would take a lot of time and money. Before genetic
treatments to increase muscle size and strength are tried in humans,
the US Food and Drug Administration would require demonstrations
that the proposed treatment is safe and effective. This will ensure
regulatory oversight of any initial experiments along these lines
The initial steps in applying to normal humans the kinds of genetic
approaches to increasing muscle size and strength described here
will likely be performed in the course of using these procedures
to treat human muscle diseases. Clinical trials of regulated mIGF-1
gene delivery as a treatment for specific forms of muscular dystrophy
may begin within the next several years (Sweeney, personal communication).
Data on route of administration, optimal dose and possible side
effects will be obtained from these clinical trials. If efficacy
is demonstrated and side effects are small, one can imagine that
many people, young as well as old, might well be interested in receiving
genetic muscle treatments to enhance muscle size and strength. Developing
a product for which the eventual potential market is 100% of the
human population will be hard to resist.
Some human contexts for future genetic muscle treatments
What would be the human significance of genetic muscle treatments
becoming safe, inexpensive and thus potentially widespread in the
future? How would it change the physical (and mental) experience
of middle and old age? Preventing the decline of skeletal muscle
size and strength in older persons would probably decrease the number
of their falls and fractures, but would it also decrease the apprehensiveness
and growing timidity that frequently accompany old age? Would such
application come to blur the distinction between being “young”
and being “old”? Would there be any changes in relations
between the generations if the young ceased to be physically superior
to the old?
How might such future genetic muscle enhancement be used by persons
between the ages of say 20 and 50? Given the popularity of body-building
and fitness today, one could imagine its use to enhance those activities,
both in competitive and non-competitive settings. The commercial
and competitive pressures to use genetic muscle treatments to build
up, maintain and repair the muscles of competitive professional
athletes in all sports would be very strong. Are not pressures to
build muscles (even using anabolic steroids) already felt by student
athletes in colleges and high schools? Since athletic competition
extends down to youth soccer and Little League baseball, would there
any place to draw a line against using genetic muscle treatments?
What would be the responsibilities of parents toward their children’s
muscle development in a society where genetic muscle treatments
were safe, inexpensive and widespread? Should parents allow their
children’s muscles to develop “naturally” through
age 20? What should they do when daughter Jenny’s soccer coach
tells them she would be a stronger player if they got her genetic
muscle treatments, or that she won’t make the team unless
she gets treated? Would untreated children become stigmatized in
a society where many others had genetic muscle treatments?
Should these biotechnological approaches be applied
to aged human muscles?
“Sarcopenia” is currently a descriptive term for the
loss of muscle size and strength that accompanies aging. It is not
yet the name of a human disease. We will have to come to some societal
judgment about whether sarcopenia is a disease, and therefore whether
biotechnological approaches to treating it are appropriately termed
Within American society, there is probably a diversity of views
about sarcopenia. One view would assert that loss of muscle strength
with age is part of the natural human condition, part of the natural
trajectory of human life. From this starting point, attempts to
delay this process are “unnatural” and therefore suspect.
At least, it would be argued, there is no moral requirement that
modern medicine move heaven and earth to fix this problem, particularly
by expensive, novel biotechnological means.
An alternative view would point to the fact that loss of muscle
strength on aging predisposes to falls and broken bones, major sources
of morbidity in the elderly. If we could prevent or delay such loss
of muscle strength and thereby decrease the frequency of broken
bones in the elderly, would not both individuals and society benefit?
Having agreed that sarcopenia puts a name on an important social
problem, doesn’t mean that we must be committed to muscle
gene injections as the solution. “Old-fashioned” approaches
such as diet and exercise are effective at slowing the loss of muscle
size and strength during aging. Would it be a good use of brainpower
and resources to develop genetic approaches to treating sarcopenia,
if in the end all it does is substitute for regular gym visits by
older persons for resistance strength training?
Genetic muscle treatments are being evaluated as possible therapies
for various dystrophic conditions of skeletal muscle. However, as
this paper points out, once such a technology is developed and applied
within the medical sphere, there will be substantial pressures to
use it in a variety of settings that are currently “beyond
therapy”. Genetic muscle treatments that go “beyond
therapy” are another example of an emerging bioethical dilemma…should
we apply our increasing knowledge of human biology to give future
generations of humans biological capabilities that past generations
- This discussion owes much to the work
(see references 9 and 10 below) of Professor H. Lee Sweeney and
his colleagues at the University of Pennsylvania and elsewhere,
and to his description and discussion of that work at the September
2002 meeting of the President’s Council on Bioethics.
- Tzankoff, S.P., and A.H. Norris, J. Appl.
Physiol. 43 (1977): 1001-1006
- The term “sarcopenia” was
first suggested by I.H. Rosenberg in 1989. It is derived from
the Greek words meaning “poverty of flesh”. See I.H.
Rosenberg. (1989) Summary Comments, Am J Clin Nutr. 50: 1231-1233.
- See, for example Haslett, J.N., et al.,
“Gene expression comparison of biopsies from Duchenne muscular
dystrophy (DMD) and normal skeletal muscle”, Proc. Nat.
Acad. Sci. USA, 99 (2002): 15000-15005
- Zammit, P.S., and J.R. Beauchamp, “The
skeletal muscle satellite cell: stem cell or son of stem cell?”,
Differentiation, 68 (2001): 193-204
- Owino, V., et al., “Age-related
loss of skeletal muscle function and the ability to express the
autocrine form of insulin-like growth factor-1 (MGF) in response
to mechanical overload”, FEBS Letters, 505 (2001): 259-263
- Brown, W.F., “A method for estimating
the number of motor units in thenar muscles and the changes in
motor unit count with aging”, J Neurol Neurosurg Psych,
35 (1972): 845-852
- Roubenoff, R. and V.A. Hughes, “Sarcopenia:
Current concepts”, The Journals of Gerontology, Biological
and Medical Sciences, Series A, 55A (2000): M716-M724
- Barton-Davis, E., et al., “Viral
mediated expression of insulin-like growth factor I blocks the
aging-related loss of skeletal muscle function”, Proc. Nat.
Acad. Sci. USA, 95 (1998): 15603-15607
- Musaro, A., et al., "Localized Igf-1 transgene expression sustains enlargement and regeneration in senescent skeletal muscle", Nature Genetics, 27 (2001): 195-200
- The source for Figure 1 was
an Internet site at http://www.sculpturegallery.com/sculpture/david.html.
- The source for Figure 2
- These images are from the
informative Internet site www.sarcopenia.com.