The Mystery of Skeletal Muscle Hypertrophy

Richard Joshua Hernandez, B.S. and Len Kravitz, Ph.D.

Introduction
Through exercise, the muscular work done against a progressively
challenging overload leads to increases in muscle mass and crosssectional area, referred to as hypertrophy. But why does a muscle
cell grow and how does it grow? Although an intense topic of
research, scientists still do not fully understand the complete (and
very complex) picture of how muscle adapts to gradually
overloading stimuli. In this article, a brief but relevant review of the
literature is presented to better understand the multifaceted
phenomenon of skeletal muscle hypertrophy.
What is Muscular Hypertrophy?
Muscular hypertrophy is an increase in muscle mass and crosssectional area (1). The increase in dimension is due to an increase in
the size (not length) of individual muscle fibers. Both cardiac (heart)
and skeletal muscle adapt to regular, increasing work loads that
exceed the preexisting capacity of the muscle fiber. With cardiac
muscle, the heart becomes more effective at squeezing blood out of
its chambers, whereas skeletal muscle becomes more efficient at
transmitting forces through tendonous attachments to bones (1).
Skeletal muscle has two basic functions: to contract to cause body
movement and to provide stability for body posture. Each skeletal
muscle must be able to contract with different levels of tension to
perform these functions. Progressive overload is a means of
applying varying and intermittent levels of stress to skeletal muscle,
making it adapt by generating comparable amounts of tension. The
muscle is able to adapt by increasing the size and amount of
contractile proteins, which comprise the myofibrils within each
muscle fiber, leading to an increase in the size of the individual
muscle fibers and their consequent force production (1).
The Physiology of Skeletal Muscle Hypertrophy
The physiology of skeletal muscle hypertrophy will explore the role
and interaction of satellite cells, immune system reactions, and
growth factor proteins (See Figure 1. for Summary).

Satellite Cells
Satellite cells function to facilitate growth, maintenance and repair
of damaged skeletal (not cardiac) muscle tissue (2). These cells are
termed satellite cells because they are located on the outer surface
of the muscle fiber, in between the sarcolemma and basal lamina
(uppermost layer of the basement membrane) of the muscle fiber.
Satellite cells have one nucleus, with constitutes most of the cell
volume.
Usually these cells are dormant, but they become activated when
the muscle fiber receives any form of trauma, damage or injury,
such as from resistance training overload. The satellite cells then
proliferate or multiply, and the daughter cells are drawn to the
damaged muscle site. They then fuse to the existing muscle fiber,
donating their nuclei to the fiber, which helps to regenerate the
muscle fiber. It is important to emphasize the point that this process
is not creating more skeletal muscle fibers (in humans), but
increasing the size and number of contractile proteins (actin and
myosin) within the muscle fiber (see Table 1. for a summary of
changes that occur to muscle fibers as they hypertrophy). This
satellite cell activation and proliferation period lasts up to 48 hours
after the trauma or shock from the resistance training session
stimulus (2).
The amount of satellite cells present within in a muscle depends on
the type of muscle. Type I or slow-twitch oxidative fibers, tend to
have a five to six times greater satellite cell content than Type II
(fast-twitch fibers), due to an increased blood and capillary supply
(2). This may be due to the fact that Type 1 muscle fibers are used
with greatest frequency, and thus, more satellite cells may be
required for ongoing minor injuries to muscle.
Immunology
As described earlier, resistance exercise causes trauma to skeletal
muscle. The immune system responds with a complex sequence of
immune reactions leading to inflammation (3). The purpose of the
inflammation response is to contain the damage, repair the damage,
and clean up the injured area of waste products.
The immune system causes a sequence of events in response to the

injury of the skeletal muscle. Macrophages, which are involved in

phagocytosis (a process by which certain cells engulf and destroy
microorganisms and cellular debris) of the damaged cells, move to
the injury site and secrete cytokines, growth factors and other
substances. Cytokines are proteins which serve as the directors of
the immune system. They are responsible for cell-to-cell
communication. Cytokines stimulate the arrival of lymphocytes,
neutrophils, monocytes, and other healer cells to the injury site to
repair the injured tissue (4).
The three important cytokines relevant to exercise are Interleukin-1
(IL-1), Interleukin-6 (IL-6), and tumor necrosis factor (TNF). These
cytokines produce most of the inflammatory response, which is the
reason they are called the inflammatory or proinflammatory
cytokines (5). They are responsible for protein breakdown, removal
of damaged muscle cells, and an increased production of
prostaglandins (hormone-like substances that help to control the
inflammation).
Growth Factors
Growth factors are highly specific proteins, which include hormones
and cytokines, that are very involved in muscle hypertrophy (6).
Growth factors stimulate the division and differentiation (acquisition
of one or more characteristics different from the original cell) of a
particular type of cell. In regard with skeletal muscle hypertrophy,
growth factors of particular interest include insulin-like growth factor
(IGF), fibroblast growth factor (FGF), and hepatocyte growth factor
(HGF). These growth factors work in conjunction with each other to
cause skeletal muscle hypertrophy.
Insulin-Like Growth Factor
IGF is a hormone that is secreted by skeletal muscle. It regulates
insulin metabolism and stimulates protein synthesis. There are two
forms, IGF-I, which causes proliferation and differentiation of
satellite cells, and IGF-II, which is responsible for proliferation of
satellite cells. In response to progressive overload resistance
exercise, IGF-I levels are substantially elevated, resulting in skeletal
muscle hypertrophy (7).

Fibroblast Growth Factor

FGF is stored in skeletal muscle. FGF has nine forms, five of which
cause proliferation and differentiation of satellite cells, leading to
skeletal muscle hypertrophy. The amount of FGF released by the
skeletal muscle is proportional to the degree of muscle trauma or
injury (8).
Hepatocyte Growth Factor
HGF is a cytokine with various different cellular functions. Specific to
skeletal muscle hypertrophy, HGF activates satellite cells and may
be responsible for causing satellite cells to migrate to the injured
area (2).
Hormones in Skeletal Muscle Hypertrophy
Hormones are chemicals which organs secrete to initiate or regulate
the activity of an organ or group of cells in another part of the body.
It should be noted that hormone function is decidedly affected by
nutritional status, foodstuff intake and lifestyle factors such as
stress, sleep, and general health. The following hormones are of
special interest in skeletal muscle hypertrophy.
Growth Hormone
Growth hormone (GH) is a peptide hormone that stimulates IGF in
skeletal muscle, promoting satellite cell activation, proliferation and
differentiation (9). However, the observed hypertrophic effects from
the additional administration of GH, investigated in GH-treated
groups doing resistance exercise, may be less credited with
contractile protein increase and more attributable to fluid retention
and accumulation of connective tissue (9).
Cortisol
Cortisol is a steroid hormone (hormones which have a steroid
nucleus that can pass through a cell membrane without a receptor)
which is produced in the adrenal cortex of the kidney. It is a stress
hormone, which stimulates gluconeogenesis, which is the formation
of glucose from sources other than glucose, such as amino acids and
free fatty acids. Cortisol also inhibits the use of glucose by most
body cells. This can initiate protein catabolism (break down), thus

freeing amino acids to be used to make different proteins, which

may be necessary and critical in times of stress.
In terms of hypertrophy, an increase in cortisol is related to an
increased rate of protein catabolism. Therefore, cortisol breaks down
muscle proteins, inhibiting skeletal muscle hypertrophy (10).
Testosterone
Testosterone is an androgen, or a male sex hormone. The primary
physiological role of androgens are to promote the growth and
development of male organs and characteristics. Testosterone
affects the nervous system, skeletal muscle, bone marrow, skin, hair
and the sex organs.
With skeletal muscle, testosterone, which is produced in significantly
greater amounts in males, has an anabolic (muscle building) effect.
This contributes to the gender differences observed in body weight
and composition between men and women. Testosterone increases
protein synthesis, which induces hypertrophy (11).
Fiber Types and Skeletal Muscle Hypertrophy
The force generated by a muscle is dependent on its size and the
muscle fiber type composition. Skeletal muscle fibers are classified
into two major categories; slow-twitch (Type 1) and fast-twitch fibers
(Type II). The difference between the two fibers can be distinguished
by metabolism, contractile velocity, neuromuscular differences,
glycogen stores, capillary density of the muscle, and the actual
response to hypertrophy (12).
Type I Fibers
Type I fibers, also known as slow twitch oxidative muscle fibers, are
primaritly responsible for maintenance of body posture and skeletal
support. The soleus is an example of a predominantly slow-twitch
muscle fiber. An increase in capillary density is related to Type I
fibers because they are more involved in endurance activities. These
fibers are able to generate tension for longer periods of time. Type I
fibers require less excitation to cause a contraction, but also
generate less force. They utilize fats and carbohydrates better
because of the increased reliance on oxidative metabolism (the
bodys complex energy system that transforms energy from the

breakdown of fuels with the assistance of oxygen) (12).

Type I fibers have been shown to hypertrophy considerably due to
progressive overload (13,15). It is interesting to note that there is an
increase in Type I fiber area not only with resistance exercise, but
also to some degree with aerobic exercise (14).
Type II Fibers
Type II fibers can be found in muscles which require greater amounts
of force production for shorter periods of time, such as the
gastrocnemius and vastus lateralis. Type II fibers can be further
classified as Type IIa and Type IIb muscle fibers.
Type IIa Fibers
Type IIa fibers, also known as fast twitch oxidative glycolytic fibers
(FOG), are hybrids between Type I and IIb fibers. Type IIa fibers carry
characteristics of both Type I and IIb fibers. They rely on both
anaerobic (reactions which produce energy that do not require
oxygen), and oxidative metabolism to support contraction (12).
With resistance training as well as endurance training, Type IIb fibers
convert into Type IIa fibers, causing an increase in the percentage of
Type IIa fibers within a muscle (13). Type IIa fibers also have an
increase in cross sectional area resulting in hypertrophy with
resistance exercise (13). With disuse and atrophy, the Type IIa fibers
convert back to Type IIb fibers.
Type IIb Fibers
Type IIb fibers are fast-twitch glycolytic fibers (FG). These fibers rely
solely on anaerobic metabolism for energy for contraction, which is
the reason they have high amounts of glycolytic enzymes. These
fibers generate the greatest amount of force due to an increase in
the size of the nerve body, axon and muscle fiber, a higher
conduction velocity of alpha motor nerves, and a higher amount of
excitement necessary to start an action potential (12). Although this
fiber type is able to generate the greatest amount of force, it is also
maintains tension for a shortesst period of time (of all the muscle
fiber types).
Type IIb fibers convert into Type IIa fibers with resistance exercise. It
is believed that resistance training causes an increase in the

oxidative capacity of the strength-trained muscle. Because Type IIa

fibers have a greater oxidative capacity than Type IIb fibers, the
change is a positive adaptation to the demands of exercise (13).
Conclusion
Muscular hypertrophy is a multidimensional process, with numerous
factors involved. It involves a complex interaction of satellite cells,
the immune system, growth factors, and hormones with the
individual muscle fibers of each muscle. Although our goals as
fitness professionals and personal trainers motivates us to learn new
and more effective ways of training the human body, the basic
understanding of how a muscle fiber adapts to an acute and chronic
training stimulus is an important educational foundation of our
profession.

Table 1. Structural Changes that Occur as a Result of Muscle Fiber

Hypertrophy
Increase in actin filaments
Increase in myosin filaments
Increase in myofibrils
Increase in sarcoplasm
Increase in muscle fiber connective tissue