International Journal of Musculoskeletal Disorders
Saitou K and Suzuki K Int J Musculoskelet Disord 3: 115.

Research Article

DOI: 10.29011/IJMD-115.1000015

The Effects of Exercise and Massage on Disuse Muscle Atrophy inSpecial Focus on Mechanical Stress
Kumiko Saitou1 and Katsuhiko Suzuki2*
Graduate School of Sport Sciences, Waseda University, Mikajima, Tokorozawa, Saitama, Japan

1

Faculty of Sport Sciences, Waseda University, Mikajima, Tokorozawa, Saitama, Japan

2

Corresponding author: Katsuhiko Suzuki, Faculty of Sport Sciences, Waseda University, Mikajima, Tokorozawa, Saitama, Japan.
Email: katsu.suzu@waseda.jp*

Citation: Saitou K and Suzuki K (2019) The Effects of Exercise and Massage on Disuse Muscle Atrophy in Special Focus on Mechanical Stress. Int J Musculoskelet Disord 3: 115. DOI: 10.29011/IJMD-115.1000015
Received Date: 28 January, 2019; Accepted Date: 13 March, 2019; Published Date: 21 March, 2019

Abstract
Physical inactivity arises from a variety of health problems, including ageing, injury, and neuromuscular diseases, andcan lead to numerous organismal disorders such as muscle atrophy. In addition to skeletal muscle atrophy, physical inactivity induces enhanced expression of pro-inflammatory factors, promoting inflammation in muscle tissues. Muscle atrophy
and inflammation progress synergistically, aggravating physical inactivity. As a result, a vicious circle is formed by physicalinactivity and muscle frailty. Physical exercise is recommended for prevention of muscle atrophy and inflammation. However, the molecular mechanisms underlying the benefits of exercise toward muscle atrophy are poorly understood. Whereas
massage is a widespread alternative intervention and is considered to provide the physiological, biomechanical, neurologicaland psychological benefits, there remain controversies in the effectiveness of massage. In this review, we describe the associations among physical exercise, disuse muscle atrophy and massage with respect to mechanical stress on muscle tissues.

Introduction
Physical inactivity, the forth leading risk factor for deathworldwide, kills more than 5 million people every year [1]. It
arises from a variety of health problems, including ageing, injury,
and neuromuscular diseases, and can lead to numerous organismal
disorders such as muscle atrophy [2]. Inflammation, which
involves enhanced expression or production of pro-inflammatory
cytokines and chemokines, has been implicated in the pathology
of disuse skeletal muscle atrophy [3,4]. Besides the chronic natureof inactivity-related inflammation [5], a vicious circle formedby physical inactivity and muscle frailty exacerbates decreasein muscle mass, resulting in irreversible deterioration of generalbodily functions. Physical exercise has anti-inflammatory effects[6,7], but the molecular mechanisms underlying the beneficial
effects of exercise to organismal homeostasis are poorly delineated,
especially with regard to its suppression of local inflammation.
This problem may partially account for the small population
participating in habitual exercise [8,9]. Massage is generally
appreciated as a pain- or inflammation-relieving procedureand is beneficial for pain relief and improvement of physicalperformance for competitive athletes and non-athletes [10,11].
Massage suppresses local inflammation [12] and prompts recovery

1from exercise-induced muscle damage [13,14]. Although we know
very little about the biochemical mechanisms behind the benefitsof massage, there is a common feature between physical exercise
and massage. They both generate local mechanical stress onorgans, tissues and cells through deformation. This review article
aims to outline the literature on disuse muscle atrophy, massage
and the role of macrophages, especially with regard to mechanicalstress. Understanding the mutual relationship during mechanicalstress will lead to identification of novel mechanisms common toboth physical activity and massage, and to develop exercise andmassage as medical therapies based on scientific evidence.

Materials and methods
We performed an online search of the journal databases
PubMed and Google Scholar. The following keywords were usedas search terms in various combinations: disuse muscle atrophy,
acute/chronic inflammation, monocyte/macrophage, monocyte
chemoattractant protein (MCP)-1, cytokine, massage, mechanicalstress and interstitial fluid flow. Articles, and articles cited in thereference lists of identified journals were selected based on theirrelevance and specificity.

Volume 3; Issue 01

Citation: Saitou K and Suzuki K (2019) The Effects of Exercise and Massage on Disuse Muscle Atrophy in Special Focus on Mechanical Stress. Int J Musculoskelet
Disord 3: 115. DOI: 10.29011/IJMD-115.1000015

Mechanisms of Disuse Skeletal Muscle Atrophy
Introduction of disuse atrophy
Disuse muscle atrophy occurs due to chronic periods ofinactivity, such as poor prognosis, bed rest and exposure tohypogravity [15-17]. Symptoms of muscle atrophy are mainly
decrease in muscle volume, mass and myofibril cross-sectional
area (CSA) and muscle weakness. Ogawa, et al. examinedmyofibril CSA in quadriceps femora’s muscle from researchsubjects after 20 days of bed rest [15]. During bed rest, myofibril
CSA decreased significantly by 3.7%. Haus et al. reported thatsimulated microgravity, utilizing either unilateral lower limb
suspension, or bed rest caused marked decreases in quadriceps
femora’s muscle volume (35 days of limb suspension: -9% and 90
days of bed rest: -18%) and triceps surae muscle volume (35 daysof limb suspension: -11% and 90 days of bed rest: -29%) [16].
Likewise, LeBlanc, et al. demonstrated that an evident decreasein muscle volume occurred in astronauts as a result of spaceflight(8 days of weightlessness): the triceps surae (-6.3%), anterior calf(-3.9%), hamstrings (-8.3%), quadriceps (-6.0%) and intrinsic back(-10.3%) muscles [17]. On the other hand, several experiments
have been conducted on disuse muscle atrophy using rodent
models [18, 19]. The extent of disuse muscle atrophy shown by thedecreases in gastrocnemius muscle mass amounted to 15% or 25%
after 7 days of hindlimb suspension or denervation, respectively[20]. Both the decrease in protein synthesis and the increase inprotein degradation have been shown to be involved in disusemuscle atrophy, and current works have validated elements ofboth protein synthetic and degradative pathways related to muscle
atrophy [21]. Protein turnover vary based on changes in the modesof muscle movement. The changes in physical activity stimulate
muscles to adapt, changing fiber size and protein production. The
output of these adaptive responses regulates the balance between
synthesis and degradation of proteins. When protein degradation
exceeds synthesis, atrophy is induced. Therefore, we focused on
muscle protein loss related to intracellular signalling during muscle
atrophy. Several proteolytic systems responsible for muscle wasting
involve the ubiquitin-proteasome, the lysosomal, the caspase andthe Ca2+-dependent systems [22]. In disuse atrophy, the ubiquitinproteasome system constitutes a primary signalling pathway of themetabolism, stimulating a mechanism for the selective breakdownof targeted proteins [23].

Overview of the ubiquitin-proteasome system
The ubiquitin-proteasome system is one of the pathways fortargeted protein degradation in mammalian cells. It dissolves intoa large amount of intracellular proteins during muscle remodelling,
and induces intracellular signalling pathways and physiologicalprotein turnover [24]. The system recognizes damaged and/or
misfolded proteins and tags the polypeptide ubiquitin to thesetargeted proteins. Ubiquitin-tagged proteins are consequently
dissolved by a multi-catalytic enzyme complex, 26S-proteasome[25]. In brief, protein degradation by the ubiquitin systemcomposes of a two-step reaction: conjugation of several ubiquitinsto the targeted protein and breakdown of the targeted protein by2

the 26S-proteasome [26]. Conjugation of ubiquitins to the targets
proceeds through three successive steps. Initially, the ubiquitinactivating enzyme, E1, activates ubiquitins in its C-terminal Gly.
Only one E1 protein has been discovered, an abundant 110-kDa
protein necessary for survival [25]. Next, ubiquitin-conjugating
enzymes, E2s, and ubiquitin ligases, E3s, cooperate to attach
activated ubiquitins to the targets via a peptide bond. Scores of E2
proteins have been discovered, indicating diverse functions of eachE2s depending on specific types of targeted proteins. Finally, thetargeted protein is catabolized by the 26S-proteasome complex.
The 26S-proteasome breaks the substrate in small peptides (3-5amino acid residues) in an ATP-dependent process. What happens
next to these peptides that are broken?

The ubiquitin-proteasome system in disuse muscles
During physical activity, skeletal muscles undergo
mechanical stress. Decreases in mechanical stress as a resultof muscle disuse can stimulate the ubiquitin-proteasome
system activity, altering activity-related signals. Recent studies
demonstrate that the ubiquitin-regulated signals are sensitive
to muscle use [27]. The same is true for the conditions whenmuscle contraction is decreased, including denervation [2830] immobilization [31] and gravitational unloading [23,32].
For example, two E3 proteins, atrogin-1/MAFbx and MuRF1,
were elevated during physical inactivity, including hind limb
immobilization, gravitational unloading and muscle denervation[28], whereas muscle constriction performed immediately after
immobilization instigated a decline in MAFbx and MuRF1 [31].
Reaction of the ubiquitin-proteasome system to changes in muscle
movements appears to depend on the duration and intensity of theintervention [33-35]. The changes in the reaction are anticipatedto irritate both signalling and proteolysis by degradation oftargeted proteins [27]. The myogenic transcription factor MyoD
is one such molecular player that is regulated by the ubiquitinproteasome system in muscles. The ubiquitin-proteasome systemprevents MyoD signalling by degradation of the MyoD protein[36]. Another is regulation of NF-κB signalling. NF-κB signallinghas been appreciated as a main pro-inflammatory process,regulating the secretion of other pro-inflammatory molecules likechemokines and cytokines. NF-κB is up-regulated during tissue
inflammation, and also interacts with other cytokines. Ubiquitin
conjugation targets NF-κB inhibitor proteins, I-κB [37]. Thereby,
I-κB degradation of this system causes NF-κB activation, inducing
muscle wasting [18].

Inflammation
Acute inflammation and chronic inflammation
Inflammation is the physiological response through which the
body restores tissue injury and protects itself from stimuli including
pathogens and noxious agents. Symptoms of inflammation are
redness, swelling, heat and pain. After the initial stimulus, abundant
pro-inflammatory cells migrate to the site of inflammation. The
event begins with release of chemokines and cytokines from local
cells, including macrophages, dendritic cells, vascular endothelial
Volume 3; Issue 01

Citation: Saitou K and Suzuki K (2019) The Effects of Exercise and Massage on Disuse Muscle Atrophy in Special Focus on Mechanical Stress. Int J Musculoskelet
Disord 3: 115. DOI: 10.29011/IJMD-115.1000015

cells, and interstitial fibroblasts. Neutrophils are the first proinflammatory cells to arrive at the site, causing secondary damage
by releasing proteases and reactive oxygen species (ROS) [38].
Simultaneously, neutrophils promote recruitment and activationof monocytes through the secretion of cytokines and chemokines[39,40]. Then, monocytes reached the extravascular tissue, where
they transform into macrophages. Activated macrophages (alsocalled M1, below-mentioned) accelerate the mobilization andthe activation of pro-inflammatory effector cells, leading to theactivation of NF-κB signalling by interactions with a series ofpro-inflammatory cytokines, such as IL-1β and TNF-α. Activatedmacrophages produce such pro-inflammatory cytokines, andplay a pivotal role in the onset and progression of inflammation.
Activated macrophages are enhancing the ability to phagocytose
pathogens, damaged tissues and apoptotic cells, and also produce
biologically active molecules that facilitate myoblast (e.g. satellite
cells) proliferation. Activated satellite cells begin to proliferate,
thereby supplying myonuclei for the formation of new myofibers.
Subsequently, anti-inflammatory macrophages (also called M2,
below-mentioned) contribute to tissue restoration, during whichmacrophages secrete IL-10 and transforming growth factor(TGF)-ß that dampen the initial pro-inflammatory cytokine
production. These anti-inflammatory cytokines also support
myogenesis and promote wound healing [41]. Such a phenotype
shift from pro-inflammatory to anti-inflammatory macrophages
are likely induced by engulfment of debris [42]. Prohibition of
inflammation through the removal of pro-inflammatory effector
cells allows the host to restore tissue damage. The usual outlookof the acute inflammatory pathway is successful resolution andrestoration of tissue damage, without sustained inflammation,
which can bring about scarring and chronic loss of organ function.
Acute inflammation is typically self-limiting, and the tissue isrestored to a homeostatic state. Although the accurate mechanisms
regulating the shift from pro-inflammatory to anti-inflammatory
signalling are not fully identified, the resolution pathway includes
apoptosis, anti-inflammatory cytokines, anti-oxidants and proteaseinhibitors. Notably, macrophages also play a pivotal role in thisprocess. In acute inflammation, if the effectors are eliminated,
macrophages eventually return to steady state [43]. Because theresolution process involves dynamic reactions, this process may
prolong and perpetuate inflammation. Disruption of mechanisms
can cause incomplete recovery and sustained inflammatory
conditions. The disruption was brought about by failure toeliminate pathogens, for instance. Insufficient elimination of proinflammatory cells may alter functions of immune cells, affecting
resolution-related signalling, and causing chronic inflammation.
Chronic inflammation is an extended inflammation, in which
tissue damage and recovery coexist, causing to abnormal tissue
remodelling and functional disorder. Chronic inflammation begins
as a low-grade, pre-manifest response with no symptoms ofinflammation (redness, swelling, heat and pain). However, even a
low level of inflammation may damage tissue functions. In addition,
the sustained progression of tissue damage and recovery promotes
abnormal tissue remodelling (e.g. fibrogenesis) that may ultimately
cause irreversible functional disorder [44]. A complex interplay
3

between the tissue cells and the various cells in the interstitium,including vascular cells, immune cells and fibroblasts, leads tothe process of chronic inflammation under the effects from boththe local tissue micro-environment and the rest of the systemicorgans. Particular attention is paid to monocyte/macrophagecells, which act as main effector cells in chronic inflammatory
pathways [44]. A primary function of macrophages for recovery
from inflammation is the clearance of effector cells (especiallyapoptotic granulocytes [45]) and pathogens. Insufficient clearanceof pro-inflammatory molecules by macrophages may also block theresolution, affecting resolution-related signalling and processes. In
summary, the diminished macrophage phagocytic ability results inaccumulation of damage-associated molecular patterns (DAMPs),
eventually resulting in chronic inflammation. More research isneeded to clarify how inflammation causes a loss of phagocytic
ability of macrophages in future studies.

Cytokines in acute and chronic inflammation
Inflammation is facilitated by a group of small protein,cytokines. Pro-inflammatory cytokines are classified into twogroups: Acute or Chronic Inflammation-related groups [46].
However, some cytokines, such as TNF-α, IL-1 and IL-6,
contribute to both inflammation pathways. In both acute andchronic inflammation, a variety of cytokines promote expressionof cell adhesion molecules and chemoattractant, leading toleukocyte recruitment. Furthermore, cytokines regulate theactivation of stromal cells (that is, mast cells, endothelial cells,
resident macrophages and fibroblasts) and the induced cells (thatis, neutrophils, monocytes, eosinophils and lymphocytes). Some
cytokines also mediate the systemic inflammatory response (e.g.
fever, leukocytosis and cachexia). This multi-functionality canelicit their effects locally and systemically, orchestrating the
inflammatory process.

Cytokines relating to acute inflammation
Representative cytokines involved in acute inflammation are
TNF-α, IL-1, IL-6, IL-17 and chemokines (IL-8 and MCP-1) [47].
IL-1 and TNF-α are the primary cytokines in acute inflammation.
IL-1
IL-1 is mainly secreted by fibroblasts, activated monocytes/
macrophages, keratinocytes, T cells and B cells. IL-1 activatesthe synthesis of a pyrogenic mediator, prostaglandin E2 (PGE2),
by hypothalamus [48] and promotes T cell proliferation. IL-1
also enhances the secretion of histamine from mast cells during
inflammation [49]. Histamine leads to vasodilatation and elevationof vascular permeability, which cause redness and swelling [50].
The function of IL-1 is inhibited by the IL-1 receptor antagonist(IL-1ra), which is produced by TNF-α- or GM-CSF-stimulated
neutrophils and by IL-4-stimulated macrophages [51].
TNF-α
TNF-α is mainly produced by mast cells, activatedmonocytes/macrophages, fibroblasts and natural killer (NK)cells [52]. TNF-α can also trigger fever, either directly throughpromotion of PGE2 synthesis by the hypothalamus, or indirectly
Volume 3; Issue 01

Citation: Saitou K and Suzuki K (2019) The Effects of Exercise and Massage on Disuse Muscle Atrophy in Special Focus on Mechanical Stress. Int J Musculoskelet
Disord 3: 115. DOI: 10.29011/IJMD-115.1000015

by stimulating secretion of IL-1 [48]. Both TNF-α and IL-1 canpromote the production of PGE2 and collagenase by synovial
cells, contributing to joint injury. TNF-α causes further secondary
inflammatory effects due to activation of IL-6 synthesis in several
cells, namely, the production of acute phase protein by the liver.
Like IL-1 and TNF-α, IL-6 mediates induction of fever and theacute inflammatory signalling, eventually causing the perpetuationof the inflammatory pathway through overlapping functions ofcytokines.

Cytokines relating to chronic inflammation
As the acute inflammation period is prolonged, cytokine
interactions lead to monocyte chemotaxis towards the inflammation
site, where monocytes differentiate into macrophages. Macrophages
are activated by macrophage-activating factors, such as MCP-1
and interferon (IFN)-γ, and then migration inhibition factors, such
as GM-CSF [53] and IFN-γ, keep them in the inflamed tissue.
The cells chronically elevate levels of TNF-α and IL-1, which
results in chronic inflammation. The cytokines involved in chronic
inflammation are divided into two groups: (a) the humoral immune
group (such as IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, andTGF-β), and (b) the cellular immune group (such as TNF-α, IL-1,
IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, TGF-β, IFNs and IFN-γ
inducing factor). Some typical examples are cited as follows.

The humoral immune group
IL-3
IL-3 is secreted by T cells. It promotes the differentiationof B cells and eosinophils, while it blocks lymphokine-activatedkiller cell activity [54].
IL-4
IL-4 is secreted by CD4+ T cells, basophils and mast cells.
CD4+ T cells differentiate intoTh2 cells, not Th1 cells, by IL-4. IL-4
is also a B cell growth factor, operating to switch immunoglobulinclass to IgG1 and IgE, by which B cells become to make antibodies[55,57]. IL-4 also activates production of collagen [58,59] andIL-6 [60] by fibroblasts, involving in the onset of fibrotic diseases.
Meanwhile, IL-4 also exhibits anti-inflammatory properties. It
prohibits the secretion of pro-inflammatory cytokines, by synovial
membranes of rheumatoid arthritis patients [61].

The cellular immune group
IL-2
IL-2 is secreted mainly by Th cells, acting as a growth factor
for T cells, B cells and NK cells. As it facilitates the developmentof lymphokine-activated killer cells [54,62], it regulates both
cellular and humoral immune pathways. IL-2 binds to T cells to
promote proliferation and production of lymphocytes.
IL-12
IL-12 is secreted by antigen-presenting cells such as dendritic
cells, B cells and macrophages. It is involved in the generation4

and activation of NK cells, lymphokine-activated killer cells andcytotoxic T cells, IFN-γ secretion by T cells and NK cells, anddepression of IgE synthesis [63-65].

Atrophy and inflammation
The association between disuse muscle atrophy andinflammation remains controversial. Some authors reported thatpro-inflammatory cytokines, such as TNF-α [66-69], IFN-γ and
IL-1 [69] increase ubiquitin-attaching activity in skeletal muscle.
In contrast, some authors proposed that the ubiquitin-proteasome
system facilitates activation and translocation of NF-κB into
nucleus, as well as a successive reaction that promotes expressionof genes for ubiquitin, E2/E3 proteins and proteasome [70-74]. It
has also been reported that physical exercise can lead to mitigationof systemic inflammation due to a decrease in pro-inflammatory
mediators [6,47,75], and that exercise inhibits infiltration of proinflammatory macrophages and CD8+ T cells [76], suggesting that
disuse muscle atrophy and inflammation may interact with eachother. A certainty is that disuse muscle atrophy and inflammation
exist and are linked intimately in muscle tissues.

The Role of Macrophages in Inflammation
Origin of macrophages
Macrophages are generated from three sources. The
first is the yolk sac in the embryo, where F4/80high macrophage
progenitors are yielded. Later, during fetal development, theproduction of hematopoietic stem cells shifts to the second source,
fetal liver. The third source is the bone marrow, which gives rise
to monocytes. When incompletely differentiated monocytes reachthe extravascular tissue, they transform into monocyte-derived
macrophages [77]. Macrophages exist in all organs and connective
tissues and are named accordingly for their location, such as
microglial cells, osteoclasts, alveolar macrophages and Kupffer
cells. In addition to macrophage heterogeneity in different organs
and tissues, macrophages can exhibit heterogeneity within a single
organ or tissue [78]. Moreover, in the inflammatory condition,
after macrophages have differentiated in a microenvironment,
whether they are then terminally differentiated, or whether they
are functionally flexible and able to adapt their phenotypes
depending on changes in their location, have not been elucidated.
According to a previous report, most macrophages in the adulttissues were thought to be derived from blood monocytes, which
homeostatically replenish tissue-resident macrophage populations[79]. However, studies about the origins of many tissue-resident
macrophages have proposed that local proliferation has a way inthe regeneration and maintenance of tissue-resident macrophages[80,81]. Macrophages were found to invade atrophied myofibers
in unloaded soleus muscle [82]. Because macrophages produce
multiple biological molecules involved in both pro- and antiinflammation, medical interventions targeting macrophages andmacrophage-induced signalling may open new gateways forregulating skeletal muscle atrophy and inflammatory diseases.

Volume 3; Issue 01

Citation: Saitou K and Suzuki K (2019) The Effects of Exercise and Massage on Disuse Muscle Atrophy in Special Focus on Mechanical Stress. Int J Musculoskelet
Disord 3: 115. DOI: 10.29011/IJMD-115.1000015

Chemokine family
The release of MCP-1, a member of chemokine family,is enhanced in damaged skeletal muscle for the recruitment of
monocytes/macrophages. Chemokines are typically released bypro-inflammatory cells, and are thought to provide the initiation
for the movement of monocytes/macrophages in inflammation,
which influences the activation state of immune cells [83]. These
factors are classified according to the distribution and the numberof cysteine residues near their amino terminals, being named as C,
CC, CXC or CX3C chemokines. They show variable specificity
and diverse functions. Following muscle injury or disease,chemokines and their receptors are expressed, suggesting thatthey may be essential in tissue regeneration [84,85]. M. Brigitte
et al. have reported that the tissue macrophages of skeletal muscle
are localized in the epimysium/perimysium and that they releaseMCP-1 upon muscle injury. Resident macrophages play a keyrole in the subsequent recruitment of circulating monocytes to thedamage cite [86].

Functions of macrophages
The macrophage is a major cell of the mononuclear phagocyte
system that is constructed by cells of bone marrow origin, including
circulating monocytes. During inflammation, macrophages exhibit
three major functions; (1) antigen presentation, (2) phagocytosisand (3) immunomodulation via secretion of various cytokines and
TGFs [87]. Macrophages are crucial for the initiation, persistence
and resolution of inflammation due to being controlled theiractivity in the inflammatory pathway. Activated macrophages aredeactivated by anti-inflammatory cytokines (e.g. IL-4, IL-10, IL13 and TGF-β) that are produced by macrophages. Macrophages
engage in the auto regulatory loop in the inflammatory pathway[88].

Antigen presentation
Macrophages act to present antigens for recognition by T
cells and to stimulate the activation of T cells as antigen-presenting
cells. The macrophage-cytokine-T cell axis plays a pivotal role inthe development of adaptive immunity against specific pathogens.

Phagocytosis
Macrophages engulf materials to eliminate waste and debris
and to kill invading pathogens. Macrophages express receptors,
such as mannose receptors, Toll-like receptors (TLRs), seven
α-helical transmembrane/G protein-coupled receptors and receptors
for opsonin. Those receptors exhibit functions by recognizing andbinding pathogens, eventually engulfing them [89].

Immunomodulation
Activated macrophages secrete cytokines, such as TNF-α,
IL-1, IL-6, IFN-α/ß, IL-10, IL-12, IL-18, MCP-1, CX3CL1,
urokinase and vascular endothelial growth factor (VEGF).
These molecules participate in the control of immune response
or inflammatory reaction. For example, IL-12 is a heterodimericcytokine released primarily by antigen-presenting cells that have5

important influences in the control of the inflammatory pathway.
IL-12 promotes proliferation of T cells and NK cells, stimulates
lytic function of activated T cells, and induces IFN-γ secretion by
T cells and NK cells. IL-12 has a main role in accelerating Th1
immune responses and adaptive immunity [86]. That is, IL-12
acts as a functional bridge between the initial nonspecific innate
immunity and the following antigen-specific adaptive immunity[90]. In addition, one of chemokines, MCP-1, stimulates migrationof immune cells from the blood to tissues [91].

Classification of macrophage populations: macrophage
polarization in tissue repair
Macrophages are present as functionally different populations
at different times during acute inflammation. In general, these
populations are assumed to have conflicting functions, being
either polarized towards pro-inflammatory or anti-inflammatory
activity [92]. Polarized macrophages are presently categorized
as either M1 or M2, indicating either classical or alternative
activation [93,94]. Despite this dichotomy being, it is importantthat the M1/M2 dichotomy is not sufficiently established, andthat the categorization of macrophages into these two groups isoften ambiguous. Pro-inflammatory M1 macrophages emerge
from exposure to cytokines, such as IFN-𝛾 and TNF-𝛼, in addition
to bacterial lipopolysaccharide (LPS) or endotoxin [95,96]. On
the other hand, polarization of M2 macrophages is in complete
confusion, including three possible subtypes. However, thoseexact properties are not elucidated. Alternative M2a macrophages
are generally involved in advanced stages of wound healingor regeneration, arising from being challenged by cytokines,
such as IL-4 and IL-13. M2b macrophages also exhibit an antiinflammatory function and can secrete large amounts of IL-10.
IL-10 is known to give rise to M2c macrophages, which exhibit
an anti-inflammatory function. Moreover, M2b also share many
functions with tumor-related macrophages [97]. Pro-inflammatory
M1 macrophages are found at early stages in a series of muscle
restoration after injury or pathogen infection, followed bymacrophages having characteristics of the anti-inflammatory M2phenotype [93]. At an early stage, M1 macrophages phagocytose
necrotic cell debris and, in pathogen infection, also accomplish theprocessing and display of antigens. In addition to releasing large
amounts of pro-inflammatory cytokines, M1 macrophages also
secrete iNOS, which is needed for killing intracellular pathogens.
Alternatively activated M2 macrophages exist in large quantities
during the final phase of tissue repair [98], indicating that a varietyof M2 macrophage subtypes might act during the muscle restoration
process. Despite convincing evidence for the presence of different
macrophage populations in muscle restoration, the comprehensionof their specific functions is still lacking. Furthermore, themechanisms in regulating cytokine gene silencing and macrophage
deactivation have not been completely explained yet.

Massage
Massage as an alternative medicine
Massage is one of the most widespread alternative medicine.
Volume 3; Issue 01

Citation: Saitou K and Suzuki K (2019) The Effects of Exercise and Massage on Disuse Muscle Atrophy in Special Focus on Mechanical Stress. Int J Musculoskelet
Disord 3: 115. DOI: 10.29011/IJMD-115.1000015

Recently, there has been an expansion in the use of alternative
medicine, and massage is widely appreciated by the general public[99]. Massage may be a safe and beneficial intervention devoid of
any major harms or side effects if applied by trained professionals[100]. Massage produces mechanical stress, which is expected
to increase muscle extensibility. However, despite its increasing
popularity, there remains controversy in the effectiveness of
massage as a complementary medicine.

Mechanisms of massage
Definition of Massage is “a mechanical manipulation of bodytissues with rhythmical pressure and stroking for the purpose ofpromoting health and well-being” [101]. Massage involves several
techniques, and their employment depends on the experience of theprofessional and the intended advantage [102-105]. Massage haslong been considered to contribute to wellness via physiological,
biomechanical, neurological and psychological mechanisms [105107]. So far, the speculation is that these mechanisms are exerted
through mechanostimulation and improve well-being via possible
increases in muscle blood flow, as well as possible decreases inneuromuscular excitability. Meanwhile, it has been reported
that massage does not alter blood flow for brachial and femoral
arteries [108,109], and femoral vein [109]. Inferences on otherpossible factors are required for further research to understandthe mechanisms and benefits of massage. Various physiologicalfactors are affected through massage, with the main factor being
mechanical stress. When a mechanical stress is applied to living
cells, a complex array of sensors expressing on the surface of thecells is capable of sensing and adapting to the stress. Mechanicalstress applied to those sensors activates several kinases such as
the mitogen-activated protein kinase (MAPK) and focal adhesion
kinase (FAK) family of proteins. These kinase families have further
roles in eliciting expression of regulatory factors that modulate theimmune cell recruitment, protein synthesis and glucose uptake[110-112]. Therefore, massage applied to body with diverse
mechanical stress varies degree of signalling cascade, introducing
a positive effect.

CD8 ratio were decreased, massage therapy might improve on
immune system in the HIV patients [117]. Similar findings wereobserved for children with asthma [118]. Daily 20-minute massage
for asthmatic children by their parents decreased their cortisol level
and reduced the occurrence of asthma attack. As cortisol kills NK
cells [119], the decrease in cortisol causes the increase in NK cells,
and facilitates immune function. In an animal study, following
eccentric exercise that caused myofibril damage, rabbits wereadministered a massage-like stimulation (0.5 Hz, 10 N, 15 minutes)
for 4 days [13]. Infiltration of neutrophils and macrophages into thetibialis anterior muscles, decreased and muscle hypofunction was
alleviated in the stimulation-administered groups. Furthermore,massage influences the lymphatic system. Proper lymph dynamics
are important for an effective immune system and is required tofight infection and in drainage of cell debris, excess interstitial
fluid and intestinal toxins from tissues. It is said that the lymphatic
system is positively influenced by massage [115,120,121]. It wasreported that a combination of manual massage and ultrasoundapplication modulated the swelling and fibrosis (12 sessions for 40
minutes each, 3 times/week : ultrasound therapy (Frequency of 3MHz, continuous mode, intensity of 0.8 W/cm², power of 2.8 W)
followed by the manual lymphatic drainage) [122].
Intensive exercise produces small tears in muscle fibers,leading to inflammation and soreness [123,124]. Crane et al.
reported that massage down-regulated the production of NF-κB
and pro-inflammatory cytokines such as TNF-α, thereby mitigating
dysphoria arising from exercise-induced muscle damage [14].
However, little attention has been paid to the effects of massage
on disuse-induced inflammation. Massage may have a connection
with the immune system. The improvement of the immune system
due to massage will provide the useful therapy toward various
diseases. Consequently, although the connection between massage
and ubiquitin-proteasome system for promoting disuse muscle
atrophy is not still clarified, it is quite likely that abrogation oftissue inflammation due to massage allows inhibition of disusemuscle atrophy.

Mechanical Stress on Skeletal Muscles
The Relationship between Massage and Immune
Mechanotransduction
SystemEnhancing immune function by massage
Some studies have reported that NK cells were increasedby the application of massage [113-115]. Breast cancer patientswere given massage therapy (45-minute massages, 3 times/
week for 5 weeks) [113]. In the massage therapy group, NK cells
were significantly increased. As NK cells are pivotal cytotoxic
lymphocytes in the innate immune system, the increase in cellnumbers suggests an improved immune function. Diego et al.
reported that on HIV patients, NK cells increased following
massage intervention [116]. They demonstrate that CD4 cells (cells
that are destroyed in HIV) were also increased following massage
in the HIV patients. In addition, the patients also reported that they
were less depressed by the application of massage. As depression
connects immunosuppression in which CD4 number and the CD4/
6

Skeletal muscles can sense mechanical forces and convert
them into physiological signals that regulate protein synthesis. This
energy conversion is termed mechanotransduction. To complete
this process, the unit that associates extracellular mechanical forces
with intracellular biochemical signals is required. The candidatesof the units are classified into two groups: the lipid bilayer andextracellular matrix-integrin-cytoskeleton. In this review, we
describe the extracellular matrix-integrin-cytoskeleton in thecontext of immobilization [125,126].

Extracellular matrix-integrin-cytoskeleton
Recent studies indicate that the cytoskeleton, the focal
adhesion (FA) site and dystrophin–glycoprotein complexes are
involved in mechanotransduction. The alterations in the structure of(1) FA site and (2) dystrophin-glycoprotein complex of mechanicalVolume 3; Issue 01

Citation: Saitou K and Suzuki K (2019) The Effects of Exercise and Massage on Disuse Muscle Atrophy in Special Focus on Mechanical Stress. Int J Musculoskelet
Disord 3: 115. DOI: 10.29011/IJMD-115.1000015

forces enable access to new binding sites, which in turn, activates
signalling cascade. The cascade activates MAPKs and PI3K,
ultimately leads to regulation of protein synthesis [126].

Focal adhesion site
FA sites are sites where the extracellular matrix can connect
to the intracellular cytoskeleton, and are found at neuromuscularjunctions, myotendinous junctions and customers [127]. Proteinsat FA sites possess diverse functions. One of the representative
proteins is the cell surface receptor, integrin. Integrin is comprisedof an extracellular domain, a transmembrane region and acytoplasmic domain, conjugating the extracellular matrix withcytoskeletal components [128]. The direct connection between theextracellular matrix and cytoskeletal components indicates that
integrin could become a mechanosensor that transmits extracellularmechanical forces to the inside of the cells.

Dystrophin-glycoprotein complexes
The extracellular matrix can also attach to the cytoskeleton
by the dystrophin-glycoprotein complexes. In this complex, oneof the extracellular matrix proteins, laminin, binds tightly to thetransmembranous β-dystroglycan. β-Dystroglycan constitutes
intracellular connection with dystrophin, and dystrophin establishes
a connection with F-actin. As a whole, the coupling between theinside and outside of the cell is accomplished [126].

Muscle deformation
Muscle contraction and physical load on skeletal muscles
bring about muscle deformation [129]. This deformation is a visible
change in shape without any change in volume of tissue, in whichmuscles maintain their volume. Both strains in one direction andcompressive loading cause internal stresses in skeletal muscles. The
muscles deform due to some force, either internally or externallyadministered. The most obvious mechanical changes in skeletal
muscle are associated with adhesive complexes and cytoskeleton
deformation. A cellular deformation induces mechanotransduction
in muscle tissue and mechanical stress is transmitted fromextracellular matrix to cytoskeleton [130, 131].

The relationship of mechanical stress and disuse muscle
atrophy
We conducted a series of experiments using massage-likeintervention and showed that massage-like mechanical stimulation(Local cyclical compression: 1 Hz, 30 minutes/day for 7 days)
modulated immobilization-induced pro-inflammatory responses
of macrophages in situ and alleviated muscle atrophy [132]. Whencyclical compression was applied on calves of mice with hindlimb
immobilization, the myofibril thickness and contracting forcesof calf muscles that are decreased by hindlimb immobilization
were partially restored. Notably, cyclical compression tempered
the increase in the number of cells expressing pro-inflammatory
molecules, TNF-α and MCP-1, including macrophages in situ.
Then, by using clodronate liposomes, we induced apoptotic
death of phagocytic cells in circulating blood. The reversing
effect of cyclic compression of immobilization-induced thinning7of myofibers was almost completely nullified in clodronateadministered mice. Furthermore, we validated that cyclicalcompression induced movement of intramuscular interstitial
fluid detected by µCT analysis. Then, we applied pulsatile fluid
shear stress on macrophage cells isolated from the abdominal
cavity of mice. Pulsatile fluid shear stress reduced the expressionof MCP-1 in macrophages in vitro. These results suggested thepossible involvement of mechanical stress in disuse muscle
atrophy and inflammation, and the critical role of macrophages asa mechanosensor, thereby opening a new path to develop novel
therapeutic strategies utilizing mechanical interventions.

Conclusion
Potential therapeutic role of mechanical stressMechanical stress influences every area of biology, fromearly developmental process to adult physiology and pathology. In
the adult organism, several physiological processes are dependent
on mechanical stress sensing, including the senses of hearing andtouch. There is also a dark side by pathological forces, such as
tumor metastasis and atherosclerosis [133, 134]. Endothelial
cells are found at the blood vessel interface and are continually
exposed to blood flow (i.e. mechanical stress). Therefore, researchon mechanical stress has progressed using endothelial cells as amodel system. Endothelial cells possess many mechanosensors on
the basal surfaces. These mechanosensors sense blood flow, andconvert mechanical tension into biochemical signals [135]. The
stress patterns produced by blood flow differ depending on vessel
location. These patterns vary from uniform flow to non-uniform
perturbed flow. Although endothelial cells sense and differently
react to flow patterns specific to their microenvironment, little is
known about the basal mechanisms of endothelial mechanosensing.
On the other hand, despite exposure to mechanical stress resulting
from their shape changes due to muscle contraction, there havebeen relatively few studies on the underlying mechanisms ofskeletal muscle mechanosensing. Much less work has been
conducted regarding the biological effects of mechanical stresson the immune system and macrophages. The prevailing studies
propose a possibility that monocyte/macrophage-induced
mechanic signalling affects tumor development. Mechanosensing
is the process, in which various physical stimuli of the extracellularmatrix are transduced into biochemical signals to induce cellularactions [136]. Mechanosensing pathways are activated by stimuli
to adhesion receptors (e.g. integrin and CD44), leading to changesof downstream signalling and cytoskeletal tension, ultimately
regulating many processes for induction of tumor onset andprogression [137-139]. However, the role of macrophages has notbeen made clear. Notably, adhesion receptors on macrophages canalso interact with receptors relating to inflammation by sharing
similar downstream signalling. Thus, altered extracellular matrix
characteristics can modulate immune cell actions indirectly.
Very few attempts have been made in clarifying the beneficial‘factors’ of physical exercise and massage. In this review, we
proposed that the factors were driven from the biological benefitsof mechanical stress. These findings clarified the significance of
local mechanical stress on cells in situ, which appears to be at
Volume 3; Issue 01

Citation: Saitou K and Suzuki K (2019) The Effects of Exercise and Massage on Disuse Muscle Atrophy in Special Focus on Mechanical Stress. Int J Musculoskelet
Disord 3: 115. DOI: 10.29011/IJMD-115.1000015

least partly responsible for the positive effects of physical exercise
and massage. Understanding the mechanism of mechanical stressprovides the scientific evidence for the benefits of moderate
exercise and massage and opens a new path to develop a novel
therapeutic strategy towards disuse muscle atrophy.

Acknowledgment
We would like to thank all members of the preventive
medicine laboratory. Ms. Ma, Mr. Matsumoto, Ms. Ruhee, Ms.
Kim, Mr. Tominaga and Ms. Omae gave us advice. Thanks totheir supports, we were able to finish writing this review article.
We would also like to thank Dr. Jorming Goh, Ageing ResearchInstitute for Society & Education, Nanyang Technological
University, Singapore for valuable opinions and English editing.

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Citation: Saitou K and Suzuki K (2019) The Effects of Exercise and Massage on Disuse Muscle Atrophy in Special Focus on Mechanical Stress. Int J Musculoskelet
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