PHYSIOLOGICAL MECHANISMS OF MUSCLE HYPERTROPHY

Full text

Research in Physical Education, Sport and Health
2022, Vol. 11, No. 1, pp.153-160
ISSN(Print):1857-8152; ISSN(Online):1857-8160
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PHYSIOLOGICAL MECHANISMS OF MUSCLE HYPERTROPHY
DOI:
(Original scientific paper)
Jasmina Pluncevic Gligoroska, Sanja Manchevska, Sunchica Petrovska, Beti Dejanova
Institute of Physiology, Faculty of Medicine, UKIM, Skopje, R. Macedonia
Abstract
Hypertrophy of muscle is a significant increase of the volume of muscle tissue as a result of continuous
physical activity and proper nutrition. The aim of this paper is to make a review of physiological
mechanisms which are suggested as explanations for muscle hypertrophy. A good understanding of
physiological mechanisms is needed in planning the successful strength training. The etiology of muscle
hypertrophy is thought to be based on three factors: mechanical tension (load), muscle damage, and
metabolic stress. All proposed mechanisms lead to increased muscle protein synthesis, because in order
for muscle hypertrophy to occur, it is necessary to disturb the dynamic balance between synthesis and
degradation of muscle proteins in favor of synthesis. Depending on the part of the muscle cell which
dominantly contributes to the increasing of the muscle volume hypertrophy, it could be sarcoplasmic or
miofibrilar. Cellular mechanisms which explain the hypertrophy involve the myogenic satellite cells,
several signal transducing pathways (Akt/ Mammalian Targetof rapamycin pathway; Mitogen-Activated
protein kinase pathway (MAPK); Calcium depending pathway); hormones and citokins (IgF, GH,
testosterone, insulin). Exercise has been shown to significantly increase the release of anabolic hormone
in the post workout period. The endocrine system significantly affects protein balance in muscle cells
related to adaptations to resistance training. Scientific based knowledge of muscle hypertrophy is necessary
for athletes and sport experts to design optimal training volume (load, intensity, duration, frequency, etc.)
to achieve maximal increase in muscle volume and muscle strength for better sport performance.
Key words: muscle, hypertrophy, strength training, hyperplasia
Introduction
Muscle strength is a direct indicator of muscle capacity to achieve a certain degree of tension that will
enable the muscle to perform physical activity (work). The ability of muscle to develop strength is crucial
for athletic performance. The muscle strength is correlated with the circumferential dimensions of the
muscle, its surface area, circumference or cross-section. The growth of the muscle as a result of training
with load is mainly due to the increase in the cross area of individual muscle fibers. As a result of thickening
of the muscle fibers caused by strength training regimen the whole muscle will be hypertrophied.
Hypertrophy vs hyperplasia
Hypertrophy is an increase in muscle mass and volume, which is most often caused by an exercise
program. During the hypertrophy process contractile elements enlarge and extracellular matrix expands to
support the growth (Schoenfeld, 2010). Basically, hypertrophy is the result of the growth of individual
muscle cells, and very rarely an increase in the number of cells. Muscle hypertrophy should be distinguished
from muscular hyperplasia. Hypertrophy increases the amount of contractile elements and the extracellular
matrix of the muscle cell (Virk, et al., 2000), on the other hand hyperplasia increases the number of muscle
fibers (cells) in the muscle. In almost 100 years of research into skeletal muscle structure and function,
scientists have claimed that the increase in muscle mass is the result of an increase in the diameter of already
existing muscle cells, while denying an increase in the number of muscle cells. Recent findings are
beginning to change this attitude. A meta-analysis on the topic of whether hyperplasia occurs in humans
concluded that a stretch overload consistently produced greater fiber counts while traditional training
protocols produced inconsistent results (Kelley, 1996). Numerous findings suggest that the impact of

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hyperplasia on loading-induced increases in muscle cross-sectional area is questionable and probably
minimal (Adams & Bammam, 2012).
It has been experimentally proven that longitudinal stratification of muscle cells has occurred in animals
that have been exposed to exercise (Gonyea, et al. Fahey1980). The evidence of hyperplasia in humans is
lacking and the role of hyperplasia in muscle growth is unclear. The investigation of muscle tissue in
bodybuilders shows a significantly higher number of muscle fibers in bodybuilders compared to sedentary
subjects, but there is question if these athletes have higher muscle fibers density due to the genetic
predisposition or resistance training stimulus. (Larsson & Tesch, 2003; McCall, et al., 1996)
The fundamental intervention to induce muscular hypertrophy and to increase muscle strength is
resistance exercise in combination with appropriate nutrition. The current recommendation is for
individuals to train with 40 – 80% of their 1 repetition maximum for hypertrophy or with loads 60% to
increase maximal strength (Schoenfeld et al, 2017; Wackerhageet al, 2018). Furthermore, exercisers should
perform multiple sets, rest about 2 min in-between sets, and consume a diet that contains at least 1.6 g of
protein per 1 kg body weight per day (Morton et al, 2018).
Sarcoplasmic vs myofibrillar hypertrophy
Muscle hypertrophy caused by strength training is most often the result of an increase in parallel-linked
sarcomeres and myofibrils (Schoenfeld, 2010;). As a result of skeletal muscle overload, a series of
myogenic events occur that lead to an increase in the number of myofibrils and the amount of contractile
proteins within the myofibrils. Consequently there is an increase in the total number of sarcomeres placed
in parallel. Muscle growth occurs by adding sarcomeres, increasing noncontractile elements and
sarcoplasmic fluids. Contractile hypertrophy can occur by adding sarcomeres either in parallel or in series.
Generally, in the context of traditional exercise regimen, the majority of gains in muscle mass result from
an increase of sarcomeres added in parallel (Paul, & Rosenthal, 2002,Tesch, & Larsson, 1986; Schoenfeld,
et al., 2015). Some research has shown that a certain type of exercise can lead to an increase in the number
of serially positioned sarcomeres. In the experiment in which rats worked out on a treadmill, those who ran
uphill had fewer sarcomeres than those who ran on a downhill lane. This finding suggests that repetitive
activities such as purely eccentric contractions lead to more serially connected sarcomeres. In the case of
exercise that includes only concentric contractions, a serial reduction in the length of the sarcomere occurs.
(Schoenfeld, 2010)
The sarcoplasmic hypertrophy referred to training-induced increase of various noncontractile elements
such as sarcoplasmic fluid, glycogen stores, collagen, organelles, enzymes, etc. when the muscle mass is
increased without concomitantly increasing strength (Siff, 2009). The relevance of sarcoplasmic changes,
which are characteristic for bodybuilders, is that 1g of glycogen attracts 3g of water (Chan, et al., 1982).
Physiological mechanism for hypertrophy
The elementary foundation of muscle mass increase is the increase of muscle protein synthesis (MPS).
During the individual bout of resistance training, the process of proteolysis (breakdown of proteins into
amino acids) is higher than the process of protein synthesis. During the recovery period, up to 48 hours
after exercise, muscle protein synthesis is increased 2-5 fold, which along with sufficient nutrient delivery,
results with muscle growth (Tesch, & Larsson, 1982). Muscle hypertrophy occurs when protein synthesis
is greater than the breakdown of muscle proteins. The following phenomena are characteristic of muscle
hypertrophy: increase in the number and size of myofibrils in a muscle cell; increasing of the total amount
of contractile proteins, especially myosin; and increasing of the capillary density in muscle and increasing
the amount and strength of connective, tendon and ligament tissue. Muscular adaptations are predicated on
net protein balance over time. The process is mediated by intracellular anabolic and catabolic signalling
cascades.
The etiology of muscle hypertrophy is thought to be based on three factors: mechanical tension (load),
muscle damage, and metabolic stress (Schoenfeld, 2010).
Muscle tension - mechanical stress
Most research indicates that mechanical stress is the primary initiator of the adaptive muscle response
during and after exercise training (Antonio, 2006). The muscle cell membrane has receptors which are
stimulated with mechanical stimulus, rise in the muscle tension. Mechanosensors are shown capable to
distinguish between types of mechanical stimulus, isometric, isotonic, the level of tension. Stretch induced

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mechanical loading causes the installation of sarcomeres longitudinally (i.e., in series), whereas dynamic
muscular actions increase cross-sectional area in parallel with the axes (229). Transmission of mechanical
forces occurs both longitudinally along the length of the fiber and laterally through the matrix of fascia
tissue (Street, 1983).
Mechanical tension may be the most important factor in training-induced muscle hypertrophy.
Mechanosensors are sensitive to both the magnitude and the duration of loading, and these stimuli can
directly mediate intracellular signaling to bring about hypertrophic adaptations. Investigations in animals
compared the effect of different kinds of contractions: peak concentric, eccentric, isometric and passive
stretch on different signaling pathways ( JNK – june N terminal kinase, MAPK - of mitogen-activation
protein kinase). The findings showed that eccentric contraction has the greatest effect on cell signaling,
while passive stretch showed the least effect (Martineau et al, 2001).
Modern theories suggest that the tension or mechanical stress that occurs during exercise training causes
a loss of skeletal cell integrity, causing mechanical and chemical changes at the molecular and cellular
levels in muscle and satellite cells. These complex changes result in accelerated protein synthesis. Initial
signal transduction is prolonged by the cascade activation of a number of humoral factors: growth factors,
cytokines, growth-activated channels, and focal adhesion complexes (Burridgeet al., 1997). Activation of
cellular receptors is followed by a second cycle of signal transductions that are regulated directly via the
AKT / mTOR pathway or indirectly via phosphoric acid. The importance of calcium for the process of
excitation of contractions in skeletal muscle is emphasized by the mechanisms of hypertrophy that include
Ca signaling pathways: Ca 2+ calmodulin; phosphate - calcineurin; CaMKII, CAMKIV and PKC (Chin,
2005).
Passive muscle tension that develops during eccentric contraction develops due to elongation of
extramiofibrillar elements, especially collagen in the extracellular matrix and titin (Toigo & Boutellier,
2006). This leads to an increase in active tension and a better hypertrophic response. The development of
passive tension as a hypertrophic response is much more common in FT (fast twitch) muscle fibers, which
is logical from a physiological point of view, fast fibers participate in short-term and strong muscle
contractions (Prado, et al., 2005). The mechanism of muscle tension is considered essential for the
occurrence and development of hypertrophy, but it is not the only cause of muscle hypertrophy. Evidence
for this is that in certain training programs with a high degree of muscle tension, neurological adaptation
occurs without expected hypertrophy (Vising, et al. 2008; Cote, et al. 1988).
Metabolic stress
Metabolic stress is not the primary cause of muscle hypertrophy but has been shown to have a significant
hypertrophic effect. Metabolic stress in muscle occurs as a result of anaerobic metabolism and accumulation
of metabolites such as lactates, hydrogen ions, inorganic phosphate, creatine, etc. (Suga, et al., 2009).
Metabolic stress is maximized during exercise when anaerobic glycolysis is the main source of energy,
which happens when exercise is lasting about 15 to 120 seconds.
Muscle ischemia has an additional effect on metabolic stress, which together with glycolytic training
causes hormonal changes, increased cell hydration, increased growth factor activity and free radical
formation (Goto, et al., 2005; Takarada, et al., 2000). High concentrations of hydrogen ions are thought to
increase the degradation process and stimulate sympathetic nerve activity and increase the adaptive
hypertrophic response (Goto, et al., 2004).
Typical bodybuilding routines involve performing multiple sets of 8 to 12 repetitions per set with
relatively short interset rest intervals (Lambert & Flynn, 2002), have been found to increase metabolic stress
to a much greater degree than higher-intensity regimens typically employed by powerlifters (Kramer et al.,
1995).
Scientific evidence shows that training volume i.e. load, number of repetitions, and duration of rest
between intervals are important factors to induce metabolite accumulation. Gonzalez et al. [29] found that
acute bout of resistance training with moderate repetitions combined with short rest intervals (70% 1RM,
10-12 repetitions and one minute rest interval) shows significantly higher increase in blood lactate, serum
concentration of lactate dehydrogenase, growth hormone (GH) and cortisol when compared to higher loads,
low repetitions combined with longer rest intervals (90% 1RM, 3-5 repetitions and three minute rest
intervals (de Freitas et al., 2017).
During resistance training muscle contractions compress blood vessels in active muscles, and this
occlusion can lead to a reduction of oxygen levels and, consequently, resulting in a hypoxic environment

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(Tamaki et al., 1994). Hypoxic environment strongly influence the secretion of autocrine and paracrine
substances, the recruitment of fast-twitch muscle fibers, ROS production and cell swelling (Wadley,2013).
The short rest combined with low-load training might induce a high amount of metabolic stress
ultimately leading to improved muscle hypertrophy while long rest with high-load training might lead to
superior strength increases. Acute GH increases seem not to be directly correlated with muscle hypertrophy
(Fink et al., 2016).
Several factors have been proposed to explain mechanisms of metabolic stress at the level of a muscle
cell that causes a change in its volume: increased fiber recruitment, elevated hormonal response, altered
myokin production, accumulation of ROS (reactive oxygen species) and cellular swelling.
Muscle damage
Intense exercise, particularly when a person is unaccustomed to it, can cause damage to skeletal muscle
(Clarkson & Hubal, 2002). This phenomenon, commonly known as exercise-induced muscle damage
(EIMD), can be specific to just a few macromolecules of tissue or manifest as large tears in the sarcolemma,
basal lamina, and supportive connective tissue, as well as injury to contractile elements and the cytoskeleton
( SchoenfildB.,2016).
The process of training-induced muscle damage and the consequent occurrence of muscle protein
synthesis are key factors in the occurrence of muscle hypertrophy (Keefe, & Wright, 2016; Brook, et al.,
2015). A significant contribution to the understanding of these processes was made by Damas et al., who
examined changes in muscle structure and function in certain time periods after unusual strength training
(Damas, et al., 2015). Unusual - unaccustomed, refers to the intensity of the load. Examination of the
biopsied muscle was performed after the first, acute unusual training, after 3 and after 10 weeks of training
(2 times a week). Damas and colleagues found that the reaction of the muscles after the first training is
intensive damage to the microstructures of the muscles, which causes intensive synthesis of muscle proteins
after 24 hours. After 3 weeks of training, the level of muscle damage decreases as well as the level of
muscle protein synthesis. After a period of 10 weeks, muscle damage is minimal and the level of muscle
protein synthesis (MPS) is unchanged. These findings led the authors to conclude that the most intense
MPS is present due to the repair of damaged muscle microstructure but does not affect muscle hypertrophy.
MPS has the greatest impact on muscle hypertrophy after 10 weeks of training (Damas, et al., 2016).
The latest research, presented in a review paper from 2018, points out that despite the essential
achievements in research on this issue, understanding the process of muscle hypertrophy is still not
completely clear (Damas, et al., 2018). There is a thesis that in the initial phase of training with load ( 4
strength training), the increase in the cross section of the muscle is generally longer, the so-called muscle
damage (and muscle swelling), then in the next ten training sessions there is a small increase in muscle
mass and only in the final phase of training with load (after about 18 training sessions) does true muscle
hypertrophy appear. The initial increase in muscle protein synthesis (MPS) is directly related to muscle
recovery or muscle remodeling that occurs as a result of muscle damage. The increase in MPS in the later
phase of the training program is due to the reduction of muscle damage and is most intense when the damage
is minimal.
Exercise induced muscle damage can relate to several macromolecules that build a muscle cell or be the
result of damage to the structural elements of a muscle cell or supporting tissue (Schoenfeld, 2012). It is
assumed that the damage most often occurs at the level of the basic functional and structural unit of the
muscle fiber, sarcolemma and T tubular system. Due to uneven stretching or tensioning of the myofibrils
(the most common organelles in the muscle cell), the weakest sarcomeres are randomly distributed.
Deformation of the muscle membrane disrupts the integrity of the cell membrane, especially its T tubular
extensions, which leads to impaired homeostasis of Ca ions (opening of the stretch channel for Ca). The
body registers muscle cell damage as acute myotrauma and reacts to it as an acute inflammatory process.
At the site of damage, macrophages accumulate to remove decayed cell tissue and release various growth
factors that activate the proliferation and differentiation of satellite cells that allow muscle cell recovery
and additional volume growth (Toigo&Boutellier, 2006; Virk, et al. ., 2000).
Several essential factors are theorized that support the aforementioned physiological mechanism of
muscle hypertrophy: satellite cells, myogenic transduction, hormones and cytokines, and increased cell
hydration.

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Satellite cells
The structure and function of muscle tissue imposes its ability to regenerate and recover. In order for
muscle hypertrophy to occur, it is necessary to disturb the dynamic balance between synthesis and
degradation of muscle proteins in favor of synthesis. Satellite cells or so-called muscle stem cells become
active when an appropriate (sufficiently high intensity) mechanical stimulus acts on the skeletal muscle
(Vierck, J. et al., 2000). It is assumed that activated muscle satellite cells insert, donate cell nuclei to a
muscle cell (which are otherwise multinuclear cells) and thus increase the cell's capacity to produce new
contractile proteins (Gundersen, et al., 2016). In order for the muscle cell to grow, in addition to the increase
in the content of sarcoplasma and myofibrils, an increase in the number of myonuclei is necessary, which
will increase capacity of the muscle cell for protein synthesis (Barton-et al., 1999). In addition to serving
as nuclear donors, satellite cells participate with a number of myogenic regulatory factors (g) that aid muscle
recovery, regeneration, and growth (Yamamoto, et al. 2018).
Skeletal muscle as postmiotic tissue does not have the ability for significant cell replacement therefore
it develops its own way for regeneration and growing.The satellite cells or so called myogenic stem cells
reside inactive between the basal lamina and sarcolemma. When the mechanical stimulus or metabolic
stress activated them, satellite cells produced precursor cells (myoblasts) that multiply and fuse to existing
muscle fibers (Zammit, 2008; Togo and Boutelier, 2006). The satellite cells cycle is compound of several
phases: activation, differentiation, fusion and remodeling (Kenney, 2015)
Hormones and muscle hypertrophy
Exercise has been shown to significantly increase the release of anabolic hormone in the post workout
period. The endocrine system intricately affects protein balance in muscle cells related to adaptations to
resistance training.
The level of secretion of all significant anabolic hormones is magnified over a period of recovery.
Growth hormone (GH), testosterone, insulin and IGF-1 have shown elevated concentration following
hypertrophy type of resistance training (Schoenfeld, 2016). Some researchers have established hormone
hypothesis given the positive relationship between anabolic hormones and hypertrophy-type training. The
anabolic role of endogenous GH is a result of exercise induced hormonal elevation and large transient spike
in GH. Administration of supraphysiological doses of GH inhibits the postworkout stimulation of
endogenous isoforms of GH and could blunt hypertrophic effect (Ehrnborg & Rosen, 2008).
Testosteron is an androgen hormone whose anabolic effect is indisputable. Its anabolic action is
attributed to increase protein synthesis and diminish catabolism of the muscle proteins (Zhao et al., 2008).
The satellite cells are especially sensitive to testosterone and its mediating molecules because they have an
abundance of androgen receptors. Testosterone stimulates the production of growth hormone and IGF-1,
and they effect synergistically. There is evidence that the number of androgen receptors are changed as a
result of exercise, precisely right away after exercise the number of androgen receptors is reduced while
over the consequent several hours post exercise period the number of androgen receptors is significantly
increased (Vingren et al., 2010. Regulation of myoblasts receptors corresponds with elevations in
testosterone levels (Spering et al., 2009).
Another study found that chronic testosterone levels in adult men and women did not change
significantly during weight training. Although there is a change in testosterone levels in exercisers, no
physiological consequences have been reported after individual weight training (Trembley, et al., 2004).
The administration of exogenous testosterone produces a large increase in muscle mass in both men and
women regardless of age (Sinha-Hikim, 2006). The effects of testosterone are amplified when combined
with resistance training (Bhasin et al., 2001).
Insulin as a hormone which regulates the level of glucose in blood, facilitates the input of glucose to the
muscle cell, where it can be used as energy or stored as glycogen. Insulin also showed anabolic effect
through activation of the mammalian target of rapamycin (mTOR) which has a crucial role in regulating
the growth of the cell. The hypertrophic role of insulin is mainly due to its inhibitory effect on catabolic
processes in muscle cells (Kido et al., 2020).
Muscle cell hydration and muscle hypertrophy
Exercise training causes changes between the intracellular and extracellular compartments of body
fluids, and these changes depend on the type of exercise and the intensity of the training. Exercise that uses
the glycolytic pathway as an energy source and leads to lactate accumulation contributes to osmotic changes

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in skeletal muscle cells (Schoenfeld, & Contreras, 2014). Increased internal muscle cell tone as a result of
increased cell hydration acts as an internal mechanical stimulus for increased protein synthesis and
decreased proteolysis (Grant, et al., 2000). One of the presumed mechanisms for anabolic stimulus is
membrane stretching and facilitated transport of amino acids into the muscle cell which increased protein
turnover. The second mechanism assumes the involvement of some myogenic signaling pathways (Yumin
et al., 2021; Wang et al., 2021).
Summary
Although the positive effects of weight training, increasing muscle strength and muscle mass, are well
known in both sports practice and the scientific community, there are still dilemmas regarding physiological
mechanisms. The study of the mechanisms responsible for the occurrence of muscle hypertrophy caused
by exercise with exercise lasts for about five decades. Unfortunately, in recent years, this topic has been
the focus of interest of a small number of scientists. Knowing the mechanisms that cause an increase in
muscle volume and strength is important for planning strength training. Prescribing the amount of training:
load intensity, number of repetitions, number of series, duration and frequency of training, minimum
duration of the training program, depends on the knowledge of the physiological mechanisms of muscle
hypertrophy. Mechanisms of muscle hypertrophy represent mechanical, biochemical, auto-paracrine and
endocrine events that lead to increased muscle protein synthesis. The availability of numerous studies and
an understanding of the proposed mechanisms can help all stakeholders, athletes, sports workers, sports
and medical practitioners to improve muscle shape and function.
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