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Chad Workman
December 4, 2011
EXP 501
EXP 501 Hallmark Paper:
Mechanisms of Muscle Hypertrophy and their Indications on Exercise Program Variables
Exercise is widely researched and practiced in efforts to improve health and performance.
It has been shown that exercise training can induce a physiologic response that will favor
adaptation to an imposed demand. The principle of specificity states that these adaptations will
be specific the demand imposed. This suggests that different modalities of exercise training will
produce different physiological responses both acute and chronically. Hypertrophy is a term
used to describe the increase in cross sectional area (CSA) of a muscle. Increases in lean body
mass have long been pursued by recreational exercisers for aesthetic reasons as well as the well
documented improvements in muscular strength associated with increases in CSA (1,2,3,4).
Muscle Hypertrophy is also associated with improvements in performance of strength and power
sports such as Football, Track and Field, Rugby, Weightlifting, Power-lifting, and Bodybuilding
to name a few (1,4). This association of improvements in strength and power output favor the
proposal that improvements in CSA could be advantageous to athletes involved in most sporting
activities, especially those that involve large amounts of mechanical tension developed within a
muscle. These correlations also suggest that the hypertrophy of muscle should be a pursuit of all
individuals in an effort to improve health.
Hypertrophy can describe and occur via multiple physical changes to the structure and/or
content of a muscle. “Contractile Hypertrophy” describes an increase in the size of the
contractile proteins “Myosin and Actin” which are widely accepted as the proteins responsible
for mechanical shortening of a sarcomere (6). Contractile Hypertrophy can happen by adding
sarcomeres to the individual myofibrils in length or in parallel. Chronic elongation of muscles as
Chad Workman
December 4, 2011
EXP 501
well as eccentric based resistance training has been shown to increase sarcomeres in series (7,8).
Concentric resistance training is associated with adding sarcomeres in series (8). These concepts
have implications on the type of training performed and concomitant increases in performance.
An increase in the volume of the sarcoplasm of a muscle cell has been coined “sarcoplasmic
hypertrophy” and is often considered non-functional, unlike contractile hypertrophy, because of
the lack of structural change to the contractile elements of the cell (3). However, some research
suggests that increase in cell volume can stimulate other factors important to the structural
integrity of the cell as well as increase the amount of anabolic molecules within the sarcoplasm
(2). Hyperplasia is a term used to describe an increase in the total number of fibers contained
within a muscle and should be considered different than hypertrophy. There is conflicting
evidence within the academia and literature that hyperplasia occurs in humans (2). Some animal
studies have shown hyperplasia in response to exercise, but a conclusion is yet to be drawn in
research on humans.
Satellite Cells are an important factor in maintaining the homeostasis of a muscle cell.
These cells are thought to be the main mediators of muscle hypertrophy. They are located
between the basal lamina and the sarcolemma (2). Normally inactive, Satellite cells need some
sort of chemical or mechanical stimulus to become activated. Once activated, they bind to cells
and provide means that are necessary for hypertrophy (8). Satellite cells donate nuclei to the
muscle cells which can increase the protein synthesis of the cell. Furthermore, a muscle retains a
constant nuclear-content-to-fiber-mass ratio and thus an increase in either would mediate and
require an increase in the other (182).
There are also multiple myogenic pathways of muscle hypertrophy. These pathways
include a chemical response to a mechanical stimulus that will travel downstream to exert an
Chad Workman
December 4, 2011
EXP 501
anabolic effect on the muscle cell by promoting muscle hypertrophy or inhibiting catabolism.
Akt/Mammalian Target Rapamycin Pathway is an important mediator of protein synthesis and
breakdown (2,9). Akt is stimulated by mechanical stress which signals (Target of Rapamycin)
mTOR farther downstream that will have anabolic effects on muscle cells (2,9). The Mitogen
Activated Protein Kinase (MAPK) pathway is a mediator of adaptive response to a stressor. This
occurs by increasing mRNA transcription and DNA repair (2). There are also other Calcium
dependent pathways in which Calcineurin (Cn) signals other factors that play a crucial role in
hypertrophic response (2).
Hormones are long-distance, long-acting communicators of the body. They usually have
one or more of three different effects on a cell: 1) Alter membrane transport of the cell. 2) Alter
DNA activity of the cell. 3) Activate second messengers within the cell to elicit an effect (18).
Steroid hormones are commonly associated with muscle hypertrophy and strength, but there are
many other and maybe even more important hormones involved in hypertrophy that are not
steroids. To discuss every hormone that is involved in hypertrophy would be impractical for this
paper and so a brief overview of some important hormones will be discussed. Testosterone is a
sex hormone that is produced and secreted primarily from the testes in men and ovaries in
women. Its production and release is stimulated by Luetinizing Stimulating Hormone released
by the Anterior Pituitary Gland. A post-exercise spike in testosterone has been observed in men,
especially after resistance training, but not to the same extent in women (11,12). Testosterone
binds to its particular receptors on the cell and stimulates protein synthesis within the cell.
Furthermore, an abundance of testosterone has shown to increase the number of active receptor
cites on the cell exhibiting a positive feedback that could have implications on a chronic
Chad Workman
December 4, 2011
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adaptation to resistance training that favors hypertrophy. High levels of testosterone stimulate
the production and release of Growth Hormone which is be discussed later (13).
Insulin-like-growth factor (IGF-1) is perhaps the most important hormonal regulator of
anabolism. IGF-1 acts on active Satellite cells and Schwann cells. Its name comes from its
structural similarity to Insulin. It is produced by muscles in greater quantities during exercise
and is particularly sensitive to muscle damage (10). The isoform IGF- 1Ec is also called
“mechano-growth-factor” (MGF) which is the isoform that is more sensitive to mechanical
tension, particularly eccentric exercise and directly acts to increase protein synthesis (2). IGF-1
is also implicated in the mitotic activity of satellite cells as well as the binding of satellite cells to
muscle cells (2), thus playing a factor in increasing the number of nuclei in the muscle cell and in
turn enhancing protein synthesis.
Growth Hormone (GH) is another highly active regulator of overall tissue growth. It is
produced in the Hypothalamus and released from the Anterior Pituitary gland. Unlike other
hormones, GH exerts its effects on connective tissue and bone stimulating growth on both.
Growth Hormone is also active in metabolic activity. GH has been shown to increase the
mobilization of triglycerides from fat cells and increase the cellular uptake of amino acids.
Spikes in Growth Hormone are shown post exercise of multiple types and have been implicated
in the hypertrophic response to mechanical loading (2,13). High levels of GH influence IGF-1 to
the isoform MGF (2).
Insulin is another important hormone with anabolic properties. Released from the
pancreas in response to increased levels of blood glucose, insulin acts to alter the transport of
molecules across cell membranes. Most commonly associated with glucose uptake, insulin also
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increases uptake of amino acids and free fatty acids (18). Increases in amino acids within the
cell are necessary to carry out the protein synthesis needed for hypertrophic changes. Insulin is
usually inhibited during exercise (18). A spike of insulin post-exercise along with an adequate
amount of the right amino acids along with the previously mentioned factors could lead to
muscle hypertrophy.
Mechanical Tension, muscle damage, and metabolic stress are a byproduct of resistance
training and are important stimuli of the above mentioned pathways of hypertrophy
(1,2,3,14,15,16). This damage usually occurs via an abnormal level of tension being created by
voluntary contraction. Long periods of high levels of tension are associated with very high
metabolic demands, primarily via the depletion of muscle phosphocreatine and stored glycogen.
These metabolic demands are associated with high levels of lactate accumulation and other
byproducts of glycogenolysis (16). These homeostatic disturbances have also shown to be a
stimulus of the hypertropic response of hormones, myogenic pathways, and the activity of
satellite cells.
Sarcoplasmic hypertrophy is an increase in the volume of the cytoplasm of a muscle cell.
This can be accomplished thorough multiple means. Since most of the cytoplasmic volume is
water, you can manipulate the amount of specific solutes within the cell that will influence the
water level within the cell. The most common method is to increase the amount of glucose
within the cell. Other ions can play a role in this as well, however since these ions play a role in
the membrane potential and action potential of the cell, manipulating these concentrations could
prove to negatively influence performance. Competitive bodybuilders manipulate Sodium and
Glucose concentrations in an effort to appear larger and leaner. Competitive endurance athletes
also make attempts to maximize muscle glucose stores by “carbohydrate loading”, but not in an
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attempt to increase muscularity. Instead, their purpose is to improve performance by providing
more substrate to produce ATP via glycolysis. The load imposed by increases in intracellular
volume on the cell membrane could potentially lead to adaptations in cell membrane strength and
improve performance. Also, the increase in the total amount of molecules within a cell could
provide for a greater pool of nutrients to exert hypertrophic pathways (3).
From the data presented above, one can come to some conclusions of how to elicit
muscle hypertrophy. Most of the factors listed are related to variables that can be manipulated in
training. Mechanical tension is needed to elicit hypertrophy. This tension has to be high to elicit
hypertrophy though. This is why endurance athletes that spend large amounts of time under
tension, albeit low, do not show significant hypertrophy. This is also why low load, high volume
resistance training has not been shown to extensively stimulate hypertrophy (2,3). A sufficient
amount of time has to be spent under this high level of tension. This is one explanation why very
high load, low volume training does not always elicit the same levels of hypertrophy as moderate
load, moderate intensity training (1,2,3). As mentioned before, metabolic stress can stimulate
hypertrophy (17). This alone is not sufficient enough to increase hypertrophy though, which is
also observable in the previous example of endurance athletes. Although there is a high level of
glycolytic metabolic stress, especially in biking events and mid distance runners, there is not a
hypertrophic response.
Considering all of the pathways, training to elicit hypertrophy should entail high levels of
tension and an adequate amount of time spent at that tension. This would cause considerable
muscle damage as well as metabolic stress. High load eccentric training and high load isometric
training are both non-traditional methods that would fit these requirements. Other methods could
be simply accumulating enough repetitions under a moderate load to elicit hypertrophy. This is
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what has made up several training methodologies including: HIT, bodybuilding split training,
German volume training, Escalating Density Training (EDT), etc. While the area of hypertrophy
has been widely researched, certain aspects of training response are not totally clear. It is likely
that responses to training will vary between individuals due to genetic differences and other
behavior factors. However, extensive research has shown consistent commonalities between
specific modalities of training and the proposed methods of training listed above would be an
appropriate prescription of training for those seeking muscle hypertrophy.
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