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Researched
and Composed by
Jacob Wilson, BSc. (Hons), MSc. CSCS
Introduction
Growth Hormone (GH) is the primary pituitary hormone responsible for the
regulation of somatic (whole body) growth (Florini, Ewton, and Coolican,
1996). Experimentation began 50 years ago to examine the growth
promoting effects of GH (Murphy, Daughaday, and Hartnett, 1956).
Specifically, it was found that rats with an attenuated ability to
produce GH compromised growth in costal cartilage. However, in vitro
(when a tissue is studied in isolation outside of the organism) GH
administration to costal cartilage had minimal effect, suggesting that
GH was acting indirectly on cartilage. This led to the Somatomedin
Hypothesis which suggested that somatic growth by GH was controlled by a
secondary substance (Daughaday, and Reeder, 1966). Daughaday et al.
(1972) introduced the term Somatomedin to describe the growth promoting
effects of this substance. Nearly 20 years following the original
hypothesis, Rinderknecht and Humbel (1978) isolated Insulin Like Growth
Factor 1 (IGF-1) and found it to be the Somatomedin substance regulated
by GH.
Experimental evidence strongly supports the implication that GH and
IGF-1 are two of the primary hormones involved in skeletal muscle
growth (Palmer et al.,1994; Cuneo et
al., Beshyah, 1995; Rodriguez-Arnao et al., 1999; Whitehead et al,
Perrone et al., 1995, Jennishe and Hansson, 1987, Jennishe, 1989, Edwall
et al., 1989; Jurasinski and Veri, 1995).
This was demonstrated by McCall et al. (1999) who found that acute GH
increases after resistance training over 33 sessions in college age men
had a 0.74 correlation with muscular hypertrophy! While several
indicators of increased IGF-1 availability have been correlated to
muscle mass (Eliakim et al., 1996, 2001). In this context, the purpose
of this paper is to review the role of GH and IGF-1 in muscular
hypertrophy. The paper is divided into three sections—one pertaining to
mechanisms of muscular hypertrophy, a second to GH, and a third
pertaining to IGF-1. Each section will review the evidence for these
hormones effect on muscular hypertrophy, as well as the mechanisms for
their actions. Special care was taken to review the effect of exercise
choice, intensity, order, volume, and rest on GH and IGF-1.
Note:
The effects of GH on lipolysis, interactions with other hormones, and
nutrient partitioning have been reviewed in past articles in this
journal (Wilson
and Wilson 2005; Knowlden, 2003,
a,
b,
c)
Overview of Muscular Hypertrophy
Muscular Hypertrophy can be defined as an enlargement of muscle tissue
caused by an increase in myofibril content, non contractile protein
accretion ( i.e. mitochondria ) number, an increase in non protein based
substances such as glycogen, water, and myoglobin, and the addition of
myotubes to the periphery of a muscle cell. This article is concerned
with direct myofibrillar protein synthesis as well as peripheral size
additions to a muscle fiber.
The myofibril is a contractile unit comprised of numerous cylindrical
contractile units known as sarcomeres. Each sarcomere is linked in a
chain like fashion to form a myofibril. Finally, the sarcomere unit
itself is comprised of various contractile proteins such as actin and
myosin ( for a review of the anatomy of a muscle see Wilson, 2001 – The
Anatomy of a Muscle, and Wilson, 2003, Is The All or None Principles
Applicable to a Single Muscle Fiber? ). Net muscle protein accretion
(hypertrophy) is the result of the difference between protein synthesis
and protein degradation (see Wilson, 2005 - The Importance of Amino Acid
Shooters). Typically studies examine overall muscular protein
synthesis, or degradation increases, as well as the measurement of
specific contractile filaments synthetic rates such as actin and myosin.
Figure 1 Muscle Fiber Diagram
Figure 1 graphically depicts a microscopic viewpoint of a muscle fiber.
The
Myofibril is represented as a long cylindrical unit, and as depicted is
made of repeating subunits known as sarcomeres.
If a substance or hormone can increase protein synthesis, decrease
protein degradation, or both, a more favorable environment will occur
towards protein accretion (build up).
The enlargement of a muscle fiber appears to be attenuated (stopped)
without the fusion of myotubes to the periphery of the muscle
fiber (Allen et al, 1999; Hawke et al., 2001;
Rosenblatt et al., 1994). The
muscle fiber is a multinucleated cell (contains many nuclei). The
nucleus is the control center of a cell, and contains the instructions
for the various proteins which make up the cell’s structure. It appears
that as a muscle fiber grows, the ratio of nuclei to cell size must
remain constant (Fleck and Kraemer, 2004), this may be for the reason
that the larger muscle fibers must be able to respond to various
instructional stimuli (i.e. endocrine messengers, and mechanical
stimuli) at a greater amplitude in order to maintain its newly enlarged
structure.
Mature skeletal muscle cells are post mitotic and terminally
differentiated (Hawke and Garry, 2001),
meaning that they generally cannot divide ( evidence does suggest that
they may be able to split), or add new nuclei. In response to this
dilemma Katz (1961) discovered a class of cell, with a high nuclei to
cytoplasm ratio (the cytoplasm or intracellular environment is
relatively small, and thus the nucleus comprises much of the size of the
cell) on the periphery of the muscle fiber. Due to its location Maru
(1961) coined the term satellite cell.
Satellite cells are quiescent (dormant). However, when activated
through endocrine or mechanical stimuli they enter into two stages
necessary for muscle growth. The first is known as the proliferative
stage when Satellite cells begin to replicate
(Hawke
et al., 2001). Stimuli which induce this
are known as mitogenic stimuli (Chen et al.,
2005). An activated satellite cell is known as a myoblast,
which is committed to muscle tissue. The myoblast begins to
differentiate or change its structure such that its nucleus grows, as
well as its cytoplasm. At its full growth it is elongated and known as
a myotube, which can either fuse to an existing muscle fiber
(hypertrophy), or fuse with other myotubes to form a new muscle fiber
(hyperplasia).
To show the importance of these events, Adams (2002) investigated the
effect of inhibiting satellite cell proliferation in response to
skeletal muscular damage, and found that repair and hypertrophy were
eliminated!
In summary, muscular hypertrophy can occur through an increase in
specific contractile (or other) proteins, as well as addition of
myotubes to the periphery of the fiber. This occurs through an increase
in protein synthesis of specific proteins, or a decrease in protein
degradation. Finally, enlargement of the muscle fiber cannot occur
without addition of additional nuclei to the muscle fiber itself.
Addition of myonuclei occurs through the replication, and finally fusion
of satellite cells to the muscle fiber itself. In the end, the size to
nuclei ratio of a muscle fiber must remain relatively constant. When
this process is hindered, muscular hypertrophy is attenuated.
Growth Hormone Overview
Over 100 isoforms (variants) of GH have been identified ( King, 2003).
Of these, the most frequently occurring is the 22kDa isoform (Fleck and
Kraemer, 2004). 22kDA GH is a peptide hormone that is 191 amino acids
in length and comprises 21 % of total serum GH. Its concentration makes
it the most frequently studied isoform to infer the effect of exercise
on GH. However, recently other isoforms have been utilized and vastly
expanded the understanding of training induced GH bursts (Gosselink et
al., 1998).
GH is regulated by two hormones secreted by the hypothalamus – Growth
Hormone Releasing Hormone (GHRH) and Somatostatin (SS), which increase
and depress GH, respectively. Both of these hormones are released into a
portal system, which allows direct communication between the
hypothalamus and the anterior pituitary gland. GH is released in a
pulsatile fashion throughout the day and peaks dramatically at night
(Knowlden, 2003,
a,
b,
c for a review of the relation between GH and sleep). Its peak at
night is thought to be involved in various repair mechanisms of the body
(Knowlden, 2003,
a,
b,
c).
The actions of GH are transmitted to specific tissues after GH binds to
a Growth Hormone Receptor (GHR). The GHR is a transmembrane protein,
which means it has a binding portion on the outside of a cell, and an
aspect which faces the intracellular environment. Binding of GH to a
GHR activates a receptor associated tyrosine kinase. This is a molecule
which when activated rapidly adds phosphate groups to other molecules,
leading to a signaling cascade which ultimately activates several
specific genes.
The
Effect of Growth Hormone on Muscular Hypertrophy
GH is the primary pituitary hormone responsible for the regulation of
muscular growth (Florini, Ewton, and Coolican, 1996). A great deal of
evidence supporting this has come from studies in which GH was
inhibited. Palmer et al. (1994)
injected polycronal antiserum (anti-rGH) which inhibits GH to rats and
found that it markedly reduced the weight, total protein and RNA content
of muscles of the hind limb. However administration of GH to the rats
prevented these effects. In a second experiment anti-rGH was
administered to rats for 8 weeks. A 58 % decrease in total bodyweight
was found, while muscle mass decreased by 64%, 65% and 61% for the
plantaris, soleus and gastrocnemius respectively. These results have
generalized to humans. Cuneo et al. (1990) found that GH deficient
adults compared to a control group had reduced cross-sectional area of
thigh muscle/body weight, reduced quadriceps force/weight, and reduced
quadriceps force/muscle area, suggesting that lowered GH levels are
associated with lower skeletal muscle mass and force production
capability. In a second investigation Cuneo et al. (1991) found that
administration of GH to deficient participants reversed these muscle
wasting effects, a result which has been replicated in numerous studies
( Beshyah, 1995; Rodriguez-Arnao et al., 1999; Whitehead et al, 1992,
Cuneo, 1998).
To assess the specific effects of GH on muscle growth Fryburg, Gelfand,
and Barrett (1991) administered GH to healthy males in the brachial
artery (artery which services the arm) such that GH concentrations
increased in the brachial region, without other systemic increases. A
rapid increase in forearm muscular protein synthesis was found. In a
similar experiment Fong et al. (1989) found that exogenous GH led to an
increase in myosin heavy chain (MHC) mRNA. Myosin is a critical
contractile protein in the musculature, while a rise in mRNA reflects an
increased capacity to synthesize this protein. Studies have shown that
GH increases muscle RNA content ( the capacity for a muscle to produce
proteins) (Pell and Bates, 1991), the rate of protein synthesis per unit
of RNA (Florini, Weton, and Coolican, 1996), as well as muscle cell
amino acid uptake and transport (Cameron et al., 1988).
Growth Hormone’s Mechanisms of Action
The direct effects of GH are typically measured through in vitro
studies, in which skeletal muscle is studied outside of the body in
isolation. Such a procedure reduces the uncertainty of indirect
effects. Allen et al. (1983, 1986) investigated the effect of GH
administration twice on satellite cells in vitro in a rising dose
fashion and found that they were not stimulated to proliferate(a step
necessary for muscular hypertrophy). In other experiments both Harper
(1987) and Roe et al. (1989) investigated the effect of GH on protein
synthesis of muscle cells in vitro and found that protein synthesis was
not increased. However it was found that protein synthesis did increase
when IGF-1 was administered. These effects and others important in
muscular hypertrophy have been replicated in numerous studies (see
Florini et. al., 1996 for a review).
The above evidence suggests that GH works indirectly through IGF-1 to
facilitate muscular hypertrophy. This is known as the Somatomedin
Hypothesis (Roith et al. 2001). It is well established that GH
stimulates the release of IGF-1 from the liver (Florini et al., 1996).
In one study Bichell et al. (1992)
administered GH to hypophysectomized rats and found a dramatic rise in
hepatic (from the liver) IGF-1 mRNA within two hours, with peak values
of more than 15-fold above untreated animals by 4 hours! These results
have generalized greatly (Florini et al., 1996) including through in
vitro studies on isolated hepatocytes (Tollet et al., 1990) (liver
cells).
A subject of great debate however is the effect of GH on
muscular IGF-1 expression. This is due to a great number of
difficulties in locating GH receptors on muscle tissue (Kelly et al.,
1995). However in a break through study, Martini et al. (1995) found
mRNA for Growth Hormone Receptors in skeletal muscle tissue, providing
strong evidence for GH interaction. The effect of
GH administration on muscle IGF-1 mRNA has
been studied extensively. Within muscle tissue there have been three
isoforms of IGF-1 found, with two receiving the most study (Eliakim,
Nemet, and Cooper, 2005). The
first is IGF-1a and is similar to the IGF-1 released from liver tissue,
while the second is sensitive to mechanical stimuli and is denoted
Mechano Growth Factor (MGF). In a recent study the effect of GH on
IGF-1a and MGF in resistance trained and non resistance trained
participants was investigated (Kramer and Rogol, 2005). After five
weeks of GH administration without exercise, IGF-1a mRNA
increased 237 %, while MGF did not increase. A third group performed
exercise without GH administration and found a 163 % increase in MGF.
Finally the group which exercised and had GH administration increased
MGF by 456 %! This suggests that GH has a potent effect on non exercise
induced stimulation of IGF-1 as well as the capacity to potentiate the
effect of exercise on MGF mRNA expression.
It should be noted that a second explanation which is gaining acceptance
is the ‘Dual Effecter Theory’ proposed by Green et al (1985) which
posits that GH has both direct and indirect effects on peripheral
tissues. Evidence for this was found in the Fryburg, et al. (1991),
Barrett (1991), and Fong et al. (1989) studies mentioned previously.
They found that direct infusion of GH into the brachial arteries
increased both protein synthesis and MHC mRNA in the forearm
musculature. However, because the GH was administered in vivo, the
indirect effect of GH on muscle tissue through IGF-1 cannot be
dismissed.
In summary GH is suggested to increase circulating IGF-1 levels through
stimulating their production and secretion from the liver. It is also
suggested to increase IGF-1 in muscle tissue, as well as potentiate
mechanically stimulated MGF increase. Finally Greene et al (1985)
proposes that GH may have direct effects on skeletal muscle. However,
direct evidence for this has been sparse (Florini et al, 1996).
The
Effect of Acute Training Variables on Growth Hormone
A high correlation between acute GH release in response to exercise and
muscular hypertrophy exists (McCall et al., 1999). In this context the
effect of exercise choice, intensity, order, volume, and rest on GH will
be reviewed.
1.
Exercise Choice – This variable is related to compound vs.
isolation exercises, as well as the size of the muscle groups being
trained. In a recent review on GH, Fleck and Kramer (2004) provided
evidence that GH is released to a greater extent with compound vs.
isolation exercises, and in exercises that involve larger rather than
smaller muscle groups. Compound exercises involve movements at more
than one joint. In this context, when all other variables are held
constant a bench press which involves movement at both the elbow and
glenohumeral joints would have a greater effect than the dumbbell fly at
stimulating a GH response. Further, when comparing squats to bench
presses, the squat which involves larger muscle groups such as the
gluteals, quadriceps, and hamstrings would elicit a greater GH response
than the bench press, which mainly stimulates the pectorals and
triceps. The theoretical rationale is the fast twitch fiber feedback
hypothesis and lactate concentration hypothesis, explained under
exercise intensity.
2. Exercise Intensity – There appears to be a threshold
intensity required to stimulate an acute GH burst (Felsing et al.,
1992). Pyka et al. (1992) investigated
the effect of exercise intensity on GH response in seven young (27 years
old) individuals. Intensities consisted of 60 %, 70 % and 85 % of
participants’ 1-RM for a total of three sets on each of 12 different
exercises. No significant increase in GH was found during the 60 %
intensity condition. However, GH rose and increased progressively at
70% and 85% of 1RM. In another study
Vanhelder et al. (1984) equated work and volume, while varying
intensity. In condition one participants performed at 85 % of their max
in leg lifts for 7 repetitions over 7 sets. In condition 2 they
performed 1/3rd of this intensity for 21 repetitions for
seven sets. It was found that session one increased GH, while session
two had no significant increase in GH. What was significant about this
study was that the authors found an incredibly strong 0.99 correlation
between the amount of lactic acid produced during condition one and the
amount of GH secreted.
The above evidence lays the basis for the lactate concentration
hypothesis, which suggests that an exercise protocol will stimulate the
secretion of GH proportionally to the amount of lactate produced during
the exercise protocol (Wilson and Wilson, 2005). This hypothesis was
supported by Felsing et al. (1992) who investigated the GH response in
ten healthy male volunteers (18-35 yr) performing a ramp-type
progressive cycle-ergometer exercise for either 1, 5, or 10 minutes. In
each case intensity was varied such that participants performed either
under or over their lactate threshold (LT). It was found that GH did
not increase until participants performed over their lactate threshold
and exercised for 10 minutes ( note: the 10 minutes suggests that a
volume threshold may also exist – see below). “It has been postulated
that lactic acid indirectly stimulates GH when it disassociates into
lactate (its salt) and h+ (its acid) effectively decreasing pH. Thus, pH
may be a potent mediator of GH secretion (Wilson
and Wilson, 2005 – Slow Acting Hormones and Their Role in Exercise).”
This was supported by Gordon et al. (1994) who found that the effect of
intensity on GH was lowered when a buffer was added to increase the ph
of the blood (alkalinity group). Gorden et al. (1994) postulates that a
drop in pH elicits a general stress response by the hypothalamus which
increases GHRH and subsequent GH release. A second explanation was
provided by Sethumadhavan et al. (1991) who found that a pH of 5.0
optimally facilitated GHRH binding to the anterior pituitary gland.
The second theoretical rationale is the fast twitch motor neuron
feedback hypothesis, which posits that afferent feedback from the
activation of fast twitch motor neurons, or
feedback generated from fast twitch muscular contraction
itself is carried back to the hypothalamus or anterior pituitary gland
resulting in an increase in GH secretion. In this context, Gosselink et
al. (1998) investigated the effect of electrically stimulating slow
twitch nerve fibers for 15 minutes of distal hind limbs of rats on
bioassailable Growth Hormone (bGH), which is a distinct isoform of GH.
15 minutes of stimulation of slow nerve fibers produced no increase in
bGH. In contrast, stimulation of fast twitch nerve fibers stimulated a
250 % increase in bGH, and this rise began at 5 minutes after
stimulation! Further, there was a subsequent decrease in pituitary GH
concentration.
Intensity appears to be optimized in a moderate (70-85%) intensity
zone. Hakkinen et al. (1993) compared the effect of 20 sets of
squats using participants’ 1 repetition
maximum (1-RM) to 10 sets of participants’ 10-RM. It was found that the
1-RM condition did not produce a significant rise in GH, where as the
10-RM condition produced a dramatic rise in GH. The theoretical
rationale is that moderate intensity exercise primarily relies on
glycolysis which is responsible for the production of lactic acid.
However extremely high intensity exercise (100 % 1RM) primarily depends
on the phosphagen system. The phosphagen system liberates energy from
creatine phosphate to synthesize ATP. This process does not result in
lactic acid production ( See Wilson and Wilson, 2004 – Energetic
Transference in The Biosphere 1-3 for a review). The second theoretical
rationale is the effect of volume on GH. The 10-RM condition resulted
in more total work (volume) then the 1-RM condition (discussed in
greater detail below).
3.
Rest Periods –
Practice distribution is a critical element in designing resistance
training programs. Wilson, Wilson and King (2005, Specificity –
Practice Distribution) in an analysis found that increased rest periods
over numerous studies results in greater 1-RM gains in a criterion
task. However, hypertrophy may be optimized with shorter rest periods.
Kraemer et al (1990, 1991, 1993) in a series of studies examined the
effect of five RM sets vs. 10 RM sets
as well as 1 vs. 3 minutes of rest in each protocol, resulting in 5/1,
5/3 and 10/1, 10/3 combinations. The results demonstrated the dramatic
effect rest periods have on blood lactate concentrations. Short rest
periods significantly elevated blood lactate concentrations compared to
longer rest periods. Further, comparison of 10-RM conditions to 5 RM
conditions found that the 10 RM conditions resulted in higher blood
lactate concentrations.
This suggests that moderate intensity exercise with shorter rest periods
have the greatest effect on the acute GH response to exercise.
4. Volume – Volume is determined by the amount of sets,
repetitions, and weight lifted in a given training session. The Kraemer
et al. (1990, 1991, 1993) and Hakkinen et al. (1993) studies found that
moderate intensity exercise (10 Xs 10 RM vs. 20 Xs 1 and 10 vs. 5 RM)
resulted in a greater GH stimulus than lower
volume workouts. Gotshalk et al. (1997) investigated the effect of a
single vs. three set workout on serum GH response. It was found that
serum GH increased to a greater extent in the three set vs. single set
condition. In a similar study Mulligan et al. (1996)
investigated a two condition paradigm in which participants performed
either eight exercises, with one set per exercise (8 set condition), or
the same eight exercises, with three sets per exercise (24 set
condition). The intensity was standardized at participants’ 10 RM,
while rest was standardized at 1 minute between sets and exercises.
Growth Hormone was measured at 0, 15, and 30 minutes post exercise.
Comparison of 8 sets to 24 sets found that GH increased significantly in
the 24 set condition at 0, 15, and 30 minutes post exercise. However,
GH only increased after 15 minutes above resting in the 8 set condition,
and this increase was much lower than the 24 set condition at this same
time frame.
The above evidence suggests that volume is a powerful factor in GH
response. Moderate intensity exercise may facilitate volume due to the
greater amount of work that can be performed in a given set as compared
to a very high intensity protocol. Further, studies found increases in
GH from 1 to 3 sets, and from 8 to 24 sets. This suggests that, when
intensity is held constant, that volume may increase GH in a dose
dependent manner. However more studies need to be conducted to see how
far reaching this relationship is.
5. Exercise Order – Compound exercises with larger muscle groups
elicit the greatest GH response. In this context, performing larger
muscle group exercises first may facilitate a more anabolic response for
the remainder of the training session. Evidence suggests that GH peaks
25 minutes after a high intensity exercise
(Kramer and Olig, 2005). There are several practical
implications for this. For example, typically after a leg workout
athletes leave the weight room. However, if an athlete is prioritizing
a smaller body part, they may benefit by training it after the workout
to promote GH enriched blood flow to the muscle group. This also has
implications in full body workouts. When such workouts occur, it would
suggest that larger muscle groups should be trained before smaller to
facilitate a more anabolic hormone environment throughout the duration
of the session.
Chronic Adaptations of Growth Hormone to Exercise
Typically chronic (long term) changes in GH are inferred through
measuring resting concentrations of serum GH in trained vs. untrained
individuals. Training in a number of studies has not been found to
effect resting concentrations of 22kdGH (Kraemer et al., 1999). As an
illustration, McCall et al. (1999) investigated chronic GH responses to
resistance training in 11 college men who completed 12 weeks (33
sessions) of high volume resistance training. No differences in resting
concentrations of growth hormone (GH) were found before or after the 12
sessions.
However other methods of testing have shown differences in the acute
response of GH to trained vs. untrained individuals. In one study Craig
et al. (1989) investigated the effect of 12 weeks of resistance training
in young and elderly women. Comparison of pre and post training
conditions found that GH increased in response to exercise to a greater
extent after 12 weeks of training. The theoretical rationale is that
trained individuals possess a greater overall capacity to elicit a
necessary stimulus for increased serum GH responses to exercise (i.e.
greater volume, and lactate concentrations). Studies also suggest that
chronic training may be able to increase overnight GH amplitude. For
example Eliakim et al (1996) found a strong correlation between thigh
muscle volume, maximal O2 uptake and
circulating components of the GH in females 15-17 years of age.
Further, Kelley et al. (1990)
found a significant correlation between V02 max and GH and IGF-1 in pre
and post menopausal women. Further, it was found that even when age was
analyzed that V02 max was the only independent predictor to
significantly correlate with circulating IGF-1 levels. This suggests
that GH and IGF-1 may be effected by chronic training in some capacity,
and that elderly individuals can prevent decreases in circulating
anabolic hormones through maintaining a high level of activity.
Insulin Like Growth Factor
IGF-1 is peptide hormone synthesized in the liver, a process which takes
8-28 hours after GH stimulation (Kraemer et al., 2005). Its structure
is similar to insulin. The similarity allows IGF-1 to bind to insulin
receptors, but only at pharmacological doses. Similarly insulin can
bind to IGF-1 receptors, but with 100 times less affinity (binding
capacity) than IGF-1 itself can bind (Kraemer et al., 2005). This
peptide hormone acts mainly through IGF-I receptors. Similar to GH, the
binding of IGF-1 to an IGF-1 receptor activates a tyrosine kinase which
sets in motion a series of phosphorylations which lead to activation of
various genes, such as those coding for myofibrillar proteins. Finally,
there are six IGF binding proteins (IGF-BP), which IGF-1 is transported
in when circulating in the blood. The dominant binding protein is
IGF-BP-3 (Adams., 2003).
The Effect of Insulin Like Growth Factor-1 on Muscular
Hypertrophy
In a classic study Vandenburgh et al. (1979) found that mechanical
stimuli such as the stretching of skeletal muscle in vitro led to
increased amino acid accumulation, and increased incorporation of amino
acids into general cellular proteins and myosin heavy chains. Findings
such as this led Tidball (2005) to suggest that “ there may be
mechanisms within muscle cells through which mechanical
signals can be converted to chemical signals that generate
numerous, specific downstream events that determine muscle's
form and function “ This postulation is supported by the observation
that IGF-1 content and mRNA increase in response to various forms of
mechanical stimuli such as stretch, eccentric contractions, and injury (
Perrone et al., 1995, Jennishe and Hansson, 1987, Jennishe, 1989, Edwall
et al., 1989).
As discussed previously muscle tissue hypertrophy can occur through an
increase in protein accretion (the difference between protein synthesis
and degradation) and the addition of myotubes to the periphery of a
muscle cell.
IGF-1 is a potent stimulator of muscle protein accretion processes.
Jurasinski and Veri (1995) investigated the effect of an infusion of
IGF-1 on the gastrocnemius of septic rats and found a 2.5 fold increase
in the rate of protein synthesis. While Hong et al. (1994) found that
IGF-1 administration decreased protein degradation in muscle fibers by
14 percent, with a subsequent decrease in proteases. One of the largest
stimuli for protein degradation is found in burn victims. However
Fang et
al. (1997) and
Jurasinski et
al. (1995)
found that
IGF-1
administration both lowered protein degradation and increased protein
synthesis in burn victims.
Further
Vandenburgh et al (1991) found that in vitro IGF-I administration was
associated with a tremendous accumulation of myosin heavy chain proteins
with a subsequent increase in hypertrophy of myofibrils. This was due
to both a decrease in various.
What is also of interest is that numerous studies have shown IGF-1 to
stimulate both proliferative (mitogenic) and myogenic ( differentiation
leading to fusion of myotubes to muscle cells) processes in satellite
cells (Coolican et al., 1997, Florini et al., 1997, Robertson et al.,
1992 ).
The Response of IGF-I to Training induced Stimuli
One of the fascinating aspects of IGF-1 regulation by exercise is that
this hormone can increase through both GH dependent and independent
pathways. Serum IGF-1 changes are in large part mediated by GH
stimulation of the liver to both increase IGF-1 synthesis and secretion
(Florini et. al., 1996). However, in muscle tissue mechanical stimuli
can trigger IGF-1 increases (see above) and stimulate hypertrophy
independent of GH. This was first found in a classic study conducted by
Goldberg (1967) who investigated the compensatory hyptertrophy response
in hypophysectomized rats. Compensatory hypertrophy was stimulated by
cutting the tendon of the gastrocnemius, therefore placing greater
workload on the soleus. A significant amount of hypertrophy was found
in the soleus in only two weeks time, which to Goldberg (1967) “was
striking and had not been anticipated.” This is in large part mediated
by autocrine, mechanical stimulation of IGF-1 isoforms such as
Mechanogrowth factor in muscle tissue (Kraemer and Rogol, 2005).
Evidence suggests that mechanical stimuli serve as the mediators of
muscle growth expression of MGF, and that circulating GH concentrations
augment this process greatly (Kraemer and Rogol, 2005).
Conflicting Effects of Exercise and IGF-1 Expression
In cases several paradoxes have been found in the acute response of
circulating IGF-1 concentrations. For example, IGF-1 concentrations can
peak in as little as 10 minutes, while GH peaks in 30 minutes (Kraemer
and Rogol, 2005). This is conflicting as increases in serum
concentrations of IGF-1 occur hours after GH administration. However, a
closer look explains the situation nicely. For example exercise
stimulates fluid shifts from organs which can degrade circulating IGF-1
levels toward working musculature. Flem (1990) found that exercise
decreased blood volume in the kidneys and liver by 24 and 18 %
respectively. This is known as blood shunting. Exercise is also known
to stimulate the release of blood from the spleen which has a high
hormone concentration ( Flem, 1990 ). Further, exercise can cause
dehydration (Wilson, 2003 –Myofribrillar Hydration) which would
naturally increase the concentration of various hormones. Therefore the
immediate increases seen in IGF-1 have been found in studies, even when
the intensity was below lactate threshold, but these increases are
thought to be transient and due to fluid shifts, dehydration, release of
concentrated blood from the spleen and blood shunting.
Biphasic Response of Circulating IGF-1 concentrations to
Exercise
Muscular IGF-1 expression increases immediately to various forms of
mechanical stimuli (Perrone
et al., 1995, Jennishe and Hansson, 1987, Jennishe, 1989, Edwall et al.,
1989).
However, circulating concentrations of IGF-1 appear to respond to
exercise in a biphasic manner (Eliakim, Nemet, Cooper, 2005).
Circulating IGF-1 levels have been found to decrease in brief exercise
periods in a number of studies and increase in more chronic periods of
exercise (Sheet et al, 2002, Eliaking et al. 1996, 1998b; Eliakim et
al., 2001). As an illustration Raastad et al. (2001) found that during
a strength training program that IGF-1 was decreased after eight days of
training. While Borst et al. (2001) found that circulating IGF-1 had
increased after 13 weeks on a 25 week resistance training program. A
rapid increase in lifting capacity in the tasks used were correlated
with this rise. A second way to examine IGF-1 adaptations are through
cross sectional studies, in which individuals who have trained for long
periods of time are compared to untrained individuals. In this context
IGF-1 has been found to be positively correlated to several fitness
indexes such as cross sectional area and VO2 max
(Eliakim et al., 1996, 2001, Borer et al.
1986) again suggesting that increases in fitness are linked in
part by adaptations in the GH-IGF-Axis.
From the above evidence it appears that the first phase of circulating
IGF-1 response to training is a decrease followed by an anabolic
rebound. This may explain some of the observations observed in various
resistance training programs in which the majority of adaptations are
neural early in training programs, while latter changes ( >10 weeks)
have a much higher contribution of structural changes such as muscular
hypertrophy (Fleck and Kraemer, 2004, Sale, 1992).
Explanations for Biphasic Phase
There are two explanations for the Biphasic phase of IGF-1 response to
exercise. The first explanation is the inflammatory hypotheses (Sheet
et al., 2002). Sheet et al. (2002) suggests that the beginning phases
of an exercise program leads to a tremendous increase in serum
concentrations of various cytokines which increase inflammation. This
was seen in a study in which he had participants play 1.5 hours of
intense soccer. Proinflamatory cytokines such as tumor necrosis factor
increased, and with their increase IGF-1 decreased. Eliakim, Nemet, and
Cooper (2005) suggest that as training progresses participants make
successful adaptations to the training load, with a subsequent lowering
of pro inflammatory cytokines. As they lower the authors suggest that
it produces an ‘anabolic rebound’ as IGF-1 levels increase. It should
also be understood that IGF-1 receptors up regulate when in lower
concentrations (Lee et al., 2000) which further augments this response.
The second explanation involves the response of IGF-1 to states of
catabolism. Smith et al. (1995) investigated the effect of a 50 %
calorie restrictive diet on 8 children and 8 adults on circulating IGF-1
concentration for 6 days followed by 6 days of normal dieting. It was
found that IGF-1 concentrations decreased in both groups. These results
were also found in a protein restricted diet. Further, IGF-1 levels
returned to baseline after return to a normal diet. This result has
generalized over a number of studies (Katz et al., 2002, Ross et al.,
2000). Eliakim et al. (2005) suggests that the common link between the
findings of Smith et al. (1995) and exercise interventions which show
decreased IGF-1 levels is a state of catabolism induced by either energy
restriction, or exercise induced increases in energy expenditure above
caloric intake. To examine this hypothesis Nemet et al. (2004) had
participants perform a 7 day strenuous exercise program in which young
men were divided into two groups. One group was a positive energy
balance group in which calories consumed were greater than energy
expenditure, and a negative energy group. At the end of the seven days
the negative energy balance group lost weight(confirming a catabolic
state) and experienced a significant decrease in circulating IGF-1
levels. However, the overfed condition gained weight and experienced no
change in circulating IGF-1 levels. It should also be noted that
statistical analysis in the above study suggested that in an
isoenergetic state ( calories in = calories out) IGF-1 levels would
slightly decrease. This suggests that the Biphasic phase is both
nutrient and Cytokine dependent, and that overfeeding can attenuate the
lowering response of IGF-1 during heavy training or the start of a new
training regimen.
In summary, during catabolic states, when muscles are taxed the body
adapts by lowering IGF-1 levels, while local IGF-1 levels in the trained
musculature increase. This creates systemic catabolism, while
maintaining the possibility for local anabolism.
Theintz (1993) suggests that this attenuates somatic growth
while maintaining muscular adaptation during states of caloric
restriction. These hormonal adaptations have been seen in both female
gymnasts and wrestlers who enter states of catabolism during weight loss
periods, while still maintaining or adding musculature in the trained
regions (Jahreis et al., 1991, Roemmich and Sinning, 1997, Elokim et
al., 2005). Finally, it also explains partially why periods of
overfeeding facilitate a more whole body anabolic environment conducive
to size increases.
The Effect of Contraction Type of Local IGF-1 Response to
Training
IGF-1 appears to be sensitive to the type of contraction elicited to a
muscle group. In one study
Bamman et al. (2001)
found a significant increase (62 %) in IGF-1 mRNA concentration 48 hours
after an acute bout of eccentric but not concentric contractions! This
may be due to the reason that eccentric contractions elicit greater
myofibrillar damage than concentric contractions. This may
be why studies have found less muscle growth when eccentric activity was
inhibited during a resistance training protocol.
This suggests that techniques which emphasize the eccentric component of
a repetition may augment the hypertrophy process.
Summary
Growth Hormone and IGF-1 are primary mediators of muscular hypertrophy.
The Somatomedin hypothesis suggests that GH indirectly controls growth
through the stimulation of IGF-1 from the liver and muscle tissue.
Growth Hormone is greatly coorilated to muscular hypertrophy. For this
reason athletes will want to seek to maximize this hormone when training
for this adaptation. GH is maximized when intensity is moderate (75-85
%), and rest periods are short (1 minute). This may be due to the
reliance on glycolysis and subsequent production of lactic acid, which
has shown to sensitize the anterior pituitary hormone to GHRH. Further,
the stimulation of fast twitch fibers have also been shown to stimulate
GH secretion. In terms of volume, studies have shown that GH increases
from 1-3 and 8-24 sets, however more studies need to be conducted to see
at what point this relationship is maximized. Finally, exercises which
recruit more total muscle mass, such as bench press and squats elicit a
greater GH response than isolation exercises. In this context, it may
be valuable to perform compound before isolation exercises, as well as
train small body parts after large body parts so as to expose them to a
physiologically high concentration of GH.
IGF-1 is stimulated locally in both energy deprived and energy enriched
environments. However, circulating IGF-1 levels appear to respond to
training in a biphasic manner, with a decrease at the beginning of a
training program ( 1st few weeks) and an increase thereafter
( > 12 weeks and perhaps less). This increase is coorilated to rapid
increases in muscle mass. Further, a diet which provides a caloric
surplus attenuates the decrease found, suggesting that it may be related
to a greater increase in energy expenditure. This provides validation
for periods of overfeeding, however it also demonstrates that during
periods of caloric restriction, if protein intake is sufficient,
particularly in essential amino acids ( see Amino Acid Shooter
Breakdown) that adaptations in muscle can occur. Finally, IGF-1 is
sensitive to contraction types, with eccentric contractions eliciting
the greatest stimulus for IGF-1 muscular concentrations. This may be
attributed to the greater myofibrillar disruption elicited by eccentric
contractions.
Jacob
Wilson
jwilson@abcbodybuilding.com
President, Abcbodybuilding.com
Co Editor - The Journal of HYPERplasia Research
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