Recent Studies using an Overuse Animal Model Show that Signal

Substances are Highly Involved in Muscle Derangement and

Muscle Inflammation

Sture Forsgren

Department of Integrative Medical Biology, Section for Anatomy, Umeå University, SE-901 87, Umeå, Sweden

Keywords: Muscle Overuse, Muscle Inflammation, Exercise, Signal Substances, Tachykinins, TNF-alpha, Glutamate.

Abstract: Muscle overuse is a frequent condition accompanying sports-related activities. There is a lack of knowledge

concerning the importance of signal substances in situations when overuse leads to markedly affected

muscle structure and muscle inflammation. Recent observations on signal substance systems for the muscle

tissue in situations with muscle overuse, noted via the use of a rabbit model, are therefore here focused on.

The signal substance systems are the tachykinin system, the TNF-alpha system and the glutamate system.

The studies have shown that all three systems are involved in the myositis/muscle derangement processes

that occur. A central finding is the notion that signal substances in all three systems become locally

produced in the muscle tissue and that there is a marked presence of receptors for these in the

inflammatory/affected muscle tissue. The relevance of the findings in relation to what is known for the

systems and possibilities in treatment regimens are discussed. The findings suggest that signal substances,

more than what has been previously considered, should be taken into consideration as factors of relevance in

situations when overuse leads to structural derangement and muscle inflammation.

1 INTRODUCTION

It is well-known that sports activities related to

muscle overuse can lead to symptoms and

disabilities for the muscles. It is thus frequently

noted that overuse of muscles can lead structural

abnormalities and inflammation as well as pain

(Schoenfeld, 2012). We have in studies using an

experimental model noted that pronounced overuse

leads to a marked muscle derangement and

inflammation (myositis) (Spang et al., 2012); (Song

et al., 2012); (Forsgren et al., 2012).

Although there overall is certain knowledge

concerning affected muscles in relation to overuse,

there are still many questions to be answered

concerning the pathophysiology and treatments of

muscle derangement and myositis induced by

overuse. These conditions, accompanied by chronic

pain, can lead to the ending of sports-related

activities and can even in the long run, due to

unwanted physical inactivity, be related to

development of metabolic disorders. Via the use of

the animal model commented on above we have

obtained new information on the features that occur

within the muscle tissue during muscle

derangement/myositis and which can be important

backgrounds for the further understandings of these

conditions for human beings.

Three signal substance systems were focused on;

the tachykinin system [focus on substance P (SP)],

the TNF-alpha system and the glutamate system.

The reason for choosing the tachykinin system was

that this system is involved in pain signaling, is

upregulated in the form of increased peripheral SP-

innervation in response to muscle inflammation

((Reinert et al.,1998) and the fact that SP is known

to be pro-inflammatory (De Swert et al., 2009). The

TNF-alpha system was chosen as TNF-alpha

production has been noted for infiltrated white blood

cells in muscle tissue of patients with inflammatory

myopathies (De Bleeker et al., 1999) and in the

inflammatory cells in crush-injured and transplanted

muscle autografts in mice (Peterson et al., 2006).

Based on the findings of TNF-alpha reactions in the

muscle tissue of patients with inflammatory

myopathies, it has been suggested that TNF-alpha

may have a role in the pathogenesis of the myositis

in these diseases (Efthimiou et al., 2006). The

glutamate system was chosen as glutamate is known

to be associated with pain symptoms and as

Forsgren S..

Recent Studies using an Overuse Animal Model Show that Signal Substances are Highly Involved in Muscle Derangement and Muscle Inﬂammation.

DOI: 10.5220/0004637500640070

In Proceedings of the International Congress on Sports Science Research and Technology Support (icSPORTS-2013), pages 64-70

ISBN: 978-989-8565-79-2

 2013 SCITEPRESS (Science and Technology Publications, Lda.)

increased glutamate concentrations have been noted

for the trapezius muscle of persons with chronic

muscle pain (Flodgren et al., 2005). It is furthermore

well-known that glutamate in excess is toxic to

neurons, an excessive release of glutamate leading to

neuronal excitotoxicity and brain damage

(Matsumoto et al., 1993). Effects on oversensitive

glutamate receptors can lead to overexcitation. How

the situation is for the three signal substance systems

in response to marked muscle overuse has in

principle been unknown.

2 OUR ANIMAL MODEL

An animal model in rabbits leading to marked

overuse of the triceps surae muscle in one of the

extremities has been used. It is related to the use of

an apparatus (“kicking machine”) that leads to

passive repetitive flexions and extensions of the

right ankle joint. A pneumatic piston being attached

to the foot produces the movements. During the

plantar flexion phase, an active contraction is

furthermore induced by electrical stimulation via

surface electrodes positioned over the triceps surae

muscle. In order to obtain pronounced effects on the

tissue, the exercise regimen was for certain of the

animals coupled to local peritendinous injections

leading to pronounced effects of tachykinins. The

details of the procedures are previously published

(Song et al., 2012); (Spang et al., 2012); (Forsgren et

al., 2012).

We observed that the overuse emanating from

this experimental model leads to muscle

morphological changes that were marked and which

conformed to a distinct muscle inflammation, i.e. an

infiltration of white blood cells (a myositis process),

an increase in connective tissue and muscle fiber

changes such as fiber necrosis (Song et al., 2012).

The morphological features show resemblances to

features seen for overused muscles of humans

(Hikida et al., 1983). The marked inflammatory cell

infiltration and the fiber necrosis do to large extent

resemble the situation seen in muscle tissue in

inflammatory myopathies (De Bleeker et al., 1999).

Information on the three signal substances described

above can give hints of relevance for the situations

of marked muscle damage/myositis in man. The

advantage is that the features in very advanced

myositis/muscle derangement can be evaluated,

which is not easily done for muscle of man.

3 TACHYKININ, TNF-ALPHA

AND GLUTAMATE SYSTEMS

IN THE ANIMAL MODEL

3.1 There is an Involvement of the

Tachykinin System in the Processes

of Muscle Derangement/Myositis

The muscle derangement/myositis process was

found to be accompanied by an involvement of the

tachykinin system. There was an expression of both

tachykinin (SP) and the neurokinin-1 receptor (NK-

1R) in invading white blood cells, there was an

increased expression of tachykinin in the blood

vessel walls and an occurrence of NK-1R reactions

in these (Song et al., 2013a; 2013b). We also found

that there was an increase in tachykinin-like

immunoreactive nerve fibers as well as in NK-1R

immunoreactive nerve fibers in myositis areas.

Interestingly, there were NK-1R expressions in

muscle fibers which showed features of being in a

regenerative stage. Furthermore, NK-1R

immunoreactions and NK-1R mRNA reactions were

noted for macrophages that had extensively

infiltrated into necrotic muscle fibers (Song et al.,

2013b).

The effects in the muscle tissue can be related to

proinflammatory effects, effects which are

frequently ascribed SP (De Swert et al., 2009), and

vasoactive effects, including vasodilatory,

angiogenetic and oedema-producing effects

(Lembeck and Holzer, 1970). However, SP is also

described to be involved in trophic and proliferative

events (Pinto et al., 2010) and in healing processes

(Schmassmann et al., 2004). The findings for the

muscle fibers favour that tachykinins are involved in

necrotic processes in the muscle tissue as well as in

regenerative events. Thus, tachykinins can have

double-edged effects in muscle

derangement/myositis.

The findings show that tachykinins such as SP

have a remarkable involvement in the processes that

occur in response to muscle overuse. These are

completely new findings and which underscore that

tachykinins definitely not only are neuropeptides in

the sense that they solely are confined to the sensory

innervation but that they also are produced by cells

locally in the tissues. As these cell types were

equipped with NK-1 receptors (Song et al., 2013b),

it is likely that tachykinins have autocrine/paracrine

effects for the muscle tissue in myositis/muscle

tissue derangement.

RecentStudiesusinganOveruseAnimalModelShowthatSignalSubstancesareHighlyInvolvedinMuscleDerangement

andMuscleInflammation

3.2 There is also an Involvement of the

TNF-alpha System in the Process of

Muscle Derangement/Myositis

We have noted that there is an involvement of the

TNF-alpha system in the muscle

derangement/myositis process in the animal model.

This relates to TNF-alpha expression in invading

white blood cells, namely macrophages (Forsgren et

al., 2012). TNF-alpha mRNA was also seen for both

necrotic muscle fibers and fibers being in a

regenerative stage (Renström et al., 2013).

Interestingly, NK-1 R reactions were noted in the

same regenerating muscle fibers as those that

showed TNF-alpha mRNA and white blood cell-

related TNF-alpha mRNA and NK-1R

immunoreaction were noted in the same necrotic

muscle fibers (Renström et al., 2013). In preliminary

studies, we have noted occurrence of TNF receptor

reactions not only in infiltrated white blood cells and

aberrant muscle fibers but also in nerve fascicles in

myositis areas (unpublished observations).

Features evidencing TNF-alpha production has

never before been shown for muscle tissue in

response to marked overuse. TNF-alpha may

actually be involved in detrimental effects for the

musculature. In accordance with this suggestion,

TNF-alpha has been considered to have a damaging

role in myopathic conditions (Kondo et al., 2009)

and to be involved in the immune responses after

musculoskeletal trauma (Warren et al., 2002). It is,

however, also suggested that TNF-alpha in certain

situations can have a protective role (Echternacher et

al., 1996), and that it can be involved in the recovery

of muscle function and play a role in muscle

regeneration (Tidball, 2005). It therefore appears as

if, similarly as for tachykinins discussed above,

TNF-alpha can have a dual role in muscle

derangement.

A noteworthy feature was that there were TNF-

alpha mRNA and NK-1R immunoreactions in the

same muscle fibers, these being either necrotic or in

a regenerative stage. It thus appears as if the TNF-

alpa and tachykinin systems show interactions in the

processes of degeneration/regeneration. In

accordance with this assumption, an occurrence of

an interrelationship between the tachykinin and

TNF-alpha systems has previously been noted

(Joachim et al., 2006).

3.3 Involvement of the Glutamate

System in our Animal Model

We have also observed that the glutamate system is

involved in the myositis/muscle derangement

process. The invading white blood cells thus

exhibited reactions, both at the protein and mRNA

level, for the glutamate transporter VGluT2 (Spang

et al., 2012). Furthermore, the cells also exhibted

reactions for the glutamate receptor NMDAR1

(Spang et al., 2012). This is unexpected as the

glutamate system is mainly related to the nervous

system. Another unexpected feature previously

noted by us concerning the glutamate system is that

the tendon cells in the human Achilles tendon

exhibit reactions for VGluT2, especially so in the

tendinosis (tendinopathy) situation (Scott et al.,

2008). Our observations show that the glutamate

system is a factor to be considered for both in

myositis/muscle derangement and for tendinosis.

Ongoing studies indicate that the nerves in the

myositis areas are under influence by glutamate

(unpublished observations).

4 INTERPRETATIONS OF THE

FINDINGS; IMPLICATIONS

FOR TREATMENTS?

4.1 What do the Findings Imply for

Overuse-induced Muscle Problems

for Humans – What can we Learn,

and do the Findings Give Options

for New Treatments?

Although the animal model is not related to a

physiological situation that mimics the situations

when human beings get overuse-related problems in

their muscles, there are findings that are noteworthy

and that we can learn from. A main point is that the

model leads to very marked alterations in the form

of a pronounced myositis process, and marked

alterations in the muscle structure, including both

degenerative and regenerative features.

It was noteworthy that the signal substance

systems that were here evaluated, signal substance

systems which are known to have well established

functional importance in various situations, indeed

became involved in the muscle derangement

processes. It was namely observed that the signal

substances in these systems are locally produced

within the affected areas of the muscle tissue. This

means that there is a local supply of tachykinin,

TNF-alpha and glutamate in the muscle tissue in

these areas. The findings of receptors for all three

substances also show that they have effects in the

ongoing processes.

icSPORTS2013-InternationalCongressonSportsScienceResearchandTechnologySupport

4.2 The Good and Bad Sides of the

Systems

As is commented on above, all three systems are

related to the inflammatory process in the muscle

tissue in the sense that tachykinin, TNF-alpha and

the glutamate transporter VGluT2 all are expressed

by the invading white blood cells and that these cells

show expressions of NK-1R, TNF receptors and

glutamate receptors. It is noteworthy that there is a

large amount of evidence clarifying that tachykinins

as well as TNF-alpha can have pro-inflammatory

and deleterious effects but actually also trophic and

healing effects. How the situation is for glutamate in

this regard is more uncertain. Glutamate is mainly

considered to act as a central pain-mediating factor,

being present together with SP in primary afferents

(De Felipe et al., 1998).

It should be stressed that the inflammation as

such within muscle tissue must not in the long run

be deleterious but instead be a primary stage in the

response of the tissue, initiating the healing process.

If the inflammation is chronic and very long-lasting

there may be deficits in this restoration.

It is evident that the tachykinin system and the

TNF-alpha system both are related to fiber necrotic

as well as fiber regenerative events. This shows

further that the two systems are related to both sides

of muscle reorganization and suggests that the two

systems show interactive effects in the

reorganization.

4.3 Should Treatments that Interfere

with TNF-alpha Effects be given?

The effectiveness of antiTNF treatment is nowadays

well established not only for rheumatoid arthritis but

also for other inflammmatory disorders (Feldman

and Maini, 2003). It has also been suggested that

TNF-alpha may be a target for interfering with

myositis development (Baer, 2006). The use of

antiTNF treatment (etanercept) has actually been

shown to reduce the tissue breakdown in dystrophic

mdx mice, a model for Duchenne Muscular

Dystrophy (Hodgetts et al., 2006). Nevertheless, it is

obvious that the experience of antiTNF treatments

still is very limited concerning myositis and muscle

derangement and that more research is needed in

order to clarify if this type of treatment indeed is

beneficial in these conditions (Mastaglia, 2008).

It is evident that the question concerning the

possibility that TNF-alpha blocking could be used in

the situations of muscle derangement and myositis

can at present not be answered. A central aspect is,

as commented on above, that TNF-alpha is not only

related to deleterious effects but also trophic and

healing effects. An interesting recent finding is that

blocking of TNF-alpha primarily has effects on

nociceptive brain activity. The nociceptive CNS

activity in several brain regions, as seen via

functional MRI, was thus blocked after infusion of a

monoclonal antibody to TNFalpha (Hess et al.,

2011). This was found at an early stage, namely

before the effects on joint swelling and acute phase

reactants were noted. It is our hope that we in further

studies using our animal model can evaluate the

effects of TNF-alpha interference treatments on the

development of the myositis processes.

4.4 Should NK-1R Blockers be given?

NK-1R blockers have since long time been tested

experimentally for various conditions. They have

e.g. been found to have good effects in situations

like dextran sulfate-induced colitis in rats (Stucchi et

al., 2000). The results of more recently performed

experiments have indicated that blockade of NK-1R

signaling may be of importance in treatments of

colitis (Gad et al., 2009), oedema after traumatic

brain damage (Donkin et al., 2009) and lung injury

after smoke inhalation and burn injury (Jacob et al.,

2010). However, results obtained in clinical trials for

different conditions have to a large extent not been

convincing. A noteworthy fact is that NK-1R

blocking has not been found to induce pain

reduction. The most clear indication for which NK-1

R blocking is functioning is for the prevention of

postoperative nausea and vomiting and for inhibiting

chemotherapy-induced nausea and vomiting (Huang

and Korlipara, 2010).

It seems far-fetched at the moment to suggest

that NK-1R blocking might be effective in myositis.

As we have observed that NK-1R expression is

occurring in parallel with presence of TNF-alpha

mRNA in regenerating muscle fibers, it would really

be strange to suggest NK-1R antagonism as an

optional treatment model. If NK-1R interference

should be considered, it should probably be in the

very early stages of the derangement/inflammation

processes, remembering that SP has distinct pro-

inflammatory effects (De Swert et al., 2009). In

parallel with the plans for evaluating the

effectiveness of treatments that interfer with TNF-

alpha effects using our animal model, it is also our

intention to evaluate for the effectiveness of NK-1R

blocking in early stages of the muscle overuse.

Information we have obtained so far is that local

treatments with neutral endopeptidase and ACE

RecentStudiesusinganOveruseAnimalModelShowthatSignalSubstancesareHighlyInvolvedinMuscleDerangement

andMuscleInflammation

inhibitors, leading to more pronounced tachykinin

effects, leads to an aggravation of the muscle

derangement/myositis processes in the model

(unpublished observations).

Another possibility to reduce the effects of

tachykinin would be to use capsaicin. It is thus well-

known that capsaicin reduces the levels of SP and

that it can be used clinically as an analgetic and anti-

inflammatory agent. It is, however, unclear whether

it can be used in a condition like myositis.

4.5 Should Instead Tachykinin Agonist

Treatment be given?

It is frequently documented that SP can have wound-

healing and restorative effects. SP is e.g. shown to

accelerate intestinal regeneration after gamma-

irradiation induced damage (Kang et al., 2009).

Exogenous administration of SP is described to

enhance wound healing in a skin-injury model in

rats (Delgado et al., 2005) and SP is proposed to

promote early tissue proliferation and regulation of

nerve ingrowth in repair responses after

experimental Achilles tendon rupture in rats

(Carlsson et al., 2011). SP is also reported to be a

mechanoresponsive and autocrine regulator of

human tenocyte proliferation (Backman et al., 2011).

It is on the whole evident that the effects of

tachykinin can be double-edged. Our findings of

NK-1R in regenerating muscle fibers show that

tachykinins are related to restoration processes. On

the other hand, the injections of ACE and

endopeptidase inhibitors, leading to increased

tachykinin effects in the tissue, aggravated the

muscle derangement process.

4.6 Should Interference with Glutamat

Effects be Made?

Glutamate receptors have since long been looked

upon as novel targets for drugs (Knoepfel et al.,

1995). It is possible to interfer with glutamate effects

via medication. This has especially been discussed

for diseases like ALS, Huntington´s disease and

Alzheimer´s disease. Two examples of medications

that are used are Memantine and Remacemide, both

being NMDA receptor antagonists. NMDA receptor

antagonists are also used as anesthetics for animals

and are known to have psychotomimetic effects.

However, many clinical trials invloving NMDA

receptor antagonists have failed due to unwanted

side effects. Interestingly, NFkB antagonists have

been suggested to be therapeutic agents in

inflammatory situations with increased levels of

glutamate and/or TNFalpha (Zou and Crews, 2005).

Furthermore, injections with glutamate receptor

antagonist have in experimental studies on mice

been found to reduce responses to both SP and TNF-

alpha (Jesse et al., 2008).

4.7 Currently used Medications for

Overused/Painful Muscles and

Exercise-induced Positive Effects

for the Muscle Tissue

Some comments on currently used mediations are

here given. Non-steroidal anti-inflammatory drugs

(NSAIDs) are much used for sports active persons

when trying to cope with muscle pain and injury.

That includes situations with muscle overuse. It,

however, appears as if the potential beneficial

effects of NSAIDs in the early stages is not followed

by positive features in the long run. These drugs

have profound side effects (Stovitz and Johnson,

2013), and have detrimental effects on muscle

regeneration and can lead to an impairment on

satellite cell activity (Schoenfeld, 2012).

Besides these facts concerning medications it is

obvious that exercise as such can have positive

effects for muscle tissue. Exercise is known to have

anti-inflammatory effects. That is not least related to

effects on the systems here focused on. It is thus e.g.

shown that exercise leads to a suppression of TNF-

alpha production (Petersen and Pedersen, 2005).

Exercise-induced mechanical loading has in

experimental studies been found to involve a

function of SP in initial stages for initializing bone

formation (Ytterborg et al., 2013). Exercise has also

been shown to be effective in the induction of

ischemic tolerance for the brain via a reduction of

the mRNA levels for certain glutamatergic receptors

(Zhang et al., 2010). Physical exercise is also

associated with a release of neurotransmitters within

the brain, leading to alleviation of the pain, and a

release of endorphins from the pituitary gland.

Exercise can also lead to the creation of new neurons

as well. Exercise is on the whole known to improve

muscle strength and performance as well as oxygen

capacity (Nagaraju et al., 2000). It is suggested that

physical exercise should be prescribed as part of the

treatment

icSPORTS2013-InternationalCongressonSportsScienceResearchandTechnologySupport

5 FURTHER USE OF THE

ANIMAL MODEL; FINAL

CONCLUSIONS

There has been a lack of a model for which marked

overuse leads to affected muscle structure and

pronounced muscle inflammation. Our currently

used animal model can be used in order to further

evaluate if interference with tachykinin, TNF-alpha

and glutamate effects can limit the affection in the

muscle tissue in a situation with overuse.

A main finding in the rabbit model studies is that

there is a pronounced signal substance production

locally in the muscle tissue in response to the muscle

overuse. This fact, together with the findings of

marked occurrence of receptors for the signal

substances in the tissue, show that these substances,

more than what has been considered so far, should

be taken into consideration as factors of relevance

when overuse leads to structural affection and

marked muscle inflammation. It is hoped that

discussions at the International Congress on Sports

Science Research and Technology Support will give

new insight into the questions of the tissue changes

in muscle overuse in relation to the effects of locally

produced signal substances.

ACKNOWLEDGEMENTS

The author acknowledges the work on the muscles

in the animal model made by collaborators: Y. Song,

C. Spang, L. Renström, P. Stål, J. Yu, J. Gaida, C.

Purdam, R Lorentzon, C Backman, H. Alfredson, A.

Scott, P. Danielson.

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