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Muscle Repair

LITERATURE REVIEW

Effects of Low-Level Laser Therapy onSkeletal Muscle RepairA Systematic Review

ABSTRACT

Alves AN, Fernandes KPS, Deana AM, Bussadori SK, Mesquita-Ferrari RA:

Effects of low-level laser therapy on skeletal muscle repair: a systematic review. Am

J Phys Med Rehabil 2014;93:1073Y1085.

A review of the literature was performed to demonstrate the most current appli-

cability of low-level laser therapy (LLLT) for the treatment of skeletal muscle in-

juries, addressing different lasers, irradiation parameters, and treatment results in

animal models. Searches were performed in the PubMed/MEDLINE, SCOPUS,

and SPIE Digital Library databases for studies published from January 2006 to

August 2013 on the use of LLLT for the repair of skeletal muscle in any animal

model. All selected articles were critically appraised by two independent raters.

Seventeen of the 36 original articles on LLLTand muscle injuries met the inclusion

criteria and were critically evaluated. The main effects of LLLTwere a reduction in

the inflammatory process, the modulation of growth factors and myogenic regu-

latory factors, and increased angiogenesis. The studies analyzed demonstrate the

positive effects of LLLT on the muscle repair process, which are dependent on

irradiation and treatment parameters. The findings suggest that LLLT is an excellent

therapeutic resource for the treatment of skeletal muscle injuries in the short-term.

Key Words: Laser Therapy, Injury, Repair, Skeletal Muscle, Sports

Authors:Agnelo Neves Alves, MsCKristianne Porta Santos Fernandes, PhDAlessandro Melo Deana, PhDSandra Kalil Bussadori, PhDRaquel Agnelli Mesquita-Ferrari, PhD

Affiliations:From the Postgraduate Program inRehabilitation Sciences (ANA, KPSF,SKB, RAM-F) and PostgraduateProgram in Biophotonics Applied toHealth Sciences (KPSF, AMD, RAM-F),Universidade Nove de Julho,Sao Paulo, Brazil.

Correspondence:All correspondence and requests forreprints should be addressed to: RaquelAgnelli Mesquita-Ferrari, PhD,Departamento de Pos Graduacao,Mestrado e Doutorado em Ciencias daReabilitacao, Universidade Nove deJulho, Rua Vergueiro, 235/249,Liberdade, CEP 01504-001,Sao Paulo, Brazil.

Disclosures:Supported by UNINOVE and theBrazilian fostering agencies,Coordenacao de Aperfeicoamento dePessoal de Nıvel Superior (CAPES) andFundacao de Amparo a Pesquisa doEstado de Sao Paulo (FAPESP) (processno. 2011/17638-2).Financial disclosure statements havebeen obtained, and no conflicts ofinterest have been reported by theauthors or by any individuals in controlof the content of this article.

0894-9115/14/9312-1073American Journal of PhysicalMedicine & RehabilitationCopyright * 2014 by LippincottWilliams & Wilkins

DOI: 10.1097/PHM.0000000000000158

www.ajpmr.com LLLT and Muscle Repair 1073

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Muscle injuries are a common occurrence andcan have a major impact on the performance ofathletes and amateur sports enthusiasts.1Y3

The skeletal muscle regeneration processinvolves three major phases that function in a co-ordinated, interrelated fashion (degeneration/inflammation, repair/fibrosis, and remodeling), whichideally lead to the structural and functional recov-ery of the injured muscle.4 The initial inflammatoryphase involves the influx of cytokines, which pro-mote chemotaxis, muscle fiber necrosis (myonecrosis),the removal of necrotic tissue by macrophages,a local increase in vascularity, and the activationof myogenic precursor (stem) cells, which aredenominated satellite cells.4Y6 These cells then pro-liferate and differentiate into myoblasts, which sub-sequently fuse damaged muscle fibers to form newfunctional fibers.5Y7 The process ends with the mat-uration of new fibers, the contraction and reorgani-zation of scar tissue, and the functional recovery ofthe injured muscle.1

Although skeletal muscle has considerableregenerative capacity, the process is slow and oftenresults in some degree of functional impairmentand increased susceptibility to further injury.1,8,9

Therefore, standardized therapeutic approachesthat can accelerate and enhance the muscle repairprocess are extremely important.

In recent years, low-level laser therapy (LLLT)has emerged as an effective alternative for thetreatment of muscle injuries and has become in-creasingly common in clinical practice, especially inthe fields of physical therapy and sports medicine aswell as different fields of traditional medicine,demonstrating therapeutic effects on different typesof biologic tissues.10 Studies have reported posi-tive effects on tendinopathy,11,12 osteoarthritis,13,14

arthritis,15 wound healing,16 back pain,17,18 neckpain,19 and peripheral nerve injury.20,21 Moreover,positive effects have been reported in the treatmentof muscle injuries, such as the modulation of in-flammatory response and myonecrosis,22Y24 growthfactors,25Y27 the proliferation of satellite cells andfibroblasts,28Y31 remodeling of extracellular matrix(ECM),22,27,32,33 and angiogenesis.22,32

Despite the benefits reported in experimentsconducted in vitro, studies conducted on differentanimal models, and a number of clinical trials, di-vergent findings have been described. This is mainlybecause of the variability in the irradiation param-eters and treatment protocols used.

The aim of the present article was to performa review of the literature to demonstrate the most

current applicability of LLLT for the treatment ofskeletal muscle injuries, addressing different lasers,irradiation parameters, and treatment results inanimal models.

METHODSSearches were performed in the PubMed/

MEDLINE (Medical Literature Analysis and Re-trieval System Online), SCOPUS, and SPIE DigitalLibrary databases for original articles regarding theeffects of LLLT on skeletal muscle regeneration inexperimental models published in English fromJanuary 2006 to August 2013. The Medical SubjectHeadings and SCOPUS were used to find additionalkey words related to lasers, laser therapy, low-levellaser therapy, low intensity laser therapy, photo-therapy, or photobiomodulation; repair or regen-eration; and skeletal muscle. The bibliographies ofall retrieved articles were also examined to identifyadditional studies (Fig. 1). Two reviewers then in-dependently applied the predetermined eligibilitycriteria to the full text of the studies retrieved.

The studies selected for analysis were includedin the review when meeting the following criteria:

(1) Articles published between January 2006 andAugust 2013

(2) Animal studies involving experimental modelsof muscle injury

(3) Studies that describe or allowed the calcula-tion of the following dosimetric parameters:wavelength (lambda) in nanometers, power inmilliwatts or watts, beam spot size in squarecentimeters, power density in watts per squarecentimeter, energy density in joules per squarecentimeter, frequency in hertz, pulse in nano-seconds or duty cycle of device in percentage,treatment time in seconds, dose per treatmentsession in joules, and onset and frequency oftreatments. Total energy (joules), energy density(joules per square centimeter), and irradiationtime were obtained using traditional formulas.34

Studies were excluded on the basis of the fol-lowing criteria:

(1) In vitro studies or studies involving humansubjects

(2) Case reports or review studies(3) Noninclusion of an injury group without

treatment(4) Irradiation not performed in contact mode

(energy lost); power and other parameters not

1074 Alves et al. Am. J. Phys. Med. Rehabil. & Vol. 93, No. 12, December 2014


described, rendering the determination of thereal parameters impossible

RESULTSThe search identified 173 potentially relevant

studies. On the basis of an analysis of the abstracts,137 articles were excluded for the following reasons:nonuse of an experimental model of muscle injury(n = 18), systematic reviews (n = 11), in vitro studies(n = 2), studies not written in English (n = 2), andduplications (same study in more than one data-base; n = 104). Thirty-six studies were then selectedfor the full-text analysis, 19 of which were excludedbecause of the nondescription of irradiation pa-rameters (n = 12), nondescription of treatmentprocedures (n = 5), and noninclusion of an injurygroup not submitted to laser irradiation (n = 2).Thus, 17 articles were included for the criticalevaluation of the effectiveness of LLLT in the

treatment of muscle injuries, 15 of which used laserirradiation in the continuous mode (red spectrum[n = 5; Table 1] and infrared spectrum [n = 10;Table 2]) and 2 of which used pulsed mode (Table 3).

The studies included in this review used dif-ferent irradiation parameters to treat muscle inju-ries (Tables 1Y3). Moreover, a wide variety ofexperimental models were used to experimentallyinduce muscle injury, the most common of whichwas cryoinjury (n = 11). In all experimental models,the skeletal muscle evaluated was the only sitestudied, the most common of which was the tibialisanterior (TA) muscle (n = 16). All samples werecollected from experimental models involving lab-oratory rats (Wistar and Sprague-Dawley).

DISCUSSIONMuscle injuries constitute a major problem

faced by high-performance athletes and amateurs in

FIGURE 1 Flow diagram of study selection procedure.



TABLE

1Selectedstudiesthat

usedlaserin

continuousmode(redspectrum)

Autho

rsMuscleand

Animal

Injury

Mod

elWavelength,

nmPow

er,

mW

Beam

Spot,cm

2

Irradiation

Tim

eper

Points,secs

Energy

Density,

J/cm

2

Total

Energyper

Treatment,J

Sing

leor

Multiple

Points

Onset

and

Frequencyof

Treatment

Periods

Evaluated

Results

Rodrigu

eset

al.35

TA(W

istarrat)

Cryoinjury

660

200.04

20 50

100.4

Sing

lepo

int

48hrspostinjury,

5tim

esperweek

7,14,and

21days

jInflammatorycells

at7days

(only

with2J)

4050

2,Inflammatory

infiltrateat

14and21

days

(bothdo

ses)

jOrganizationof

musclestructure

at21

days

(both

doses,mainly

with2J)

,COX-2

mRNAat

7,14

,and

21days

(bothdo

ses)

,Myogeninand

VEGFmRNAs

at7days

(bothdo

ses)

jVE

GFmRNAat

14and21

days

(both

doses,mainly

with2J)

jMyoDmRNAat7,14

(onlywith

2J),and

21days

(bothdoses)

jMyogeninmRNA

at21

days

(only

with0.4J)

Fernandesetal.23

TA(W

istarrat)

Cryoinjury

660

200.04

105

1.6

Multiple

points

(8)

24hrspostinjury,

3tim

esperweek

1,7,

and

14days

,IL-1AmRNAat

7days

Mesqu

ita-Ferrari

etal.25

TA(W

istarrat)

Cryoinjury

660

200.04

105

1.6

Multiple

points

(8)

24hrspostinjury,

3tim

esperweek

1,7,

and

14days

,TN

F->mRNAat

1and7days

,TG

F-AmRNAat

7days

DeSo

uzaet

al.32

TA(W

istarrat)

Cryoinjury

660

200.04

105

1.6

Multiple

points

(8)

4hrspostinjury,

3tim

esperweek

1,7,

14,and

21days

,Myonecrosisat

7days

jAn

giogenesisat

7days

jDepositionof

collagentypesI

andIIIat

7days

Baptistaet

al.33

TA(W

istarrat)

Cryoinjury

660

200.04

105

1.6

Multiple

points

(8)

24hrspostinjury,

3tim

esperweek

1,7,

14,and

21days

jIm

mun

ostaining

ofcollagentype

IVat

7days



TABLE


usedlaserin

continuousmode(infraredspectrum)

Autho

rsMuscleand

Animal

Injury

Mod

elWavelength,

nmPow

er,

mW

Beam

Spot,cm

2

Irradiation

Tim

eper

Points,secs

Energy

Density,

J/cm

2

Total

Energyper

Treatment,J

Sing

leor

Multiple

Points

Onset

and

Frequencyof

Treatment

Periods

Evaluated

Results

Alveset

al.22

TA(W

istarrat)

Cryoinjury

780

400.04

1010

3.2

Multiple

points(8)

2hrspo

stinjury,

once

perday

1,3,

and

7days

,Inflammatoryinfiltrate

andmyonecrosisat

1day

jAn

giogenesisat

3and7days

jIm

maturemusclefib

ers

at7days

jMMP-2gelatinase

activity

at7days

jCollagenorganization

anddistribu

tion

at7days

Assiset

al.27

TA(W

istarrat)

Cryoinjury

808

300.0078

547

180

1.4

Sing

lepoint

Immediately

postinjury,

once

perday

4days

,Injuredarea

jMyoD,m

yogenin,

and

VEGFmRNAs

,TG

F-A1mRNA

,Depositionof

collagentype

IBrunelli

etal.36

TA(W

istarrat)

Cryoinjury

780

200.04

2010

0.4

Sing

lepoint

48hrspostinjury,

5tim

esperweek

7,14

,and

21days

,Inflammatoryinfiltrate

at7days

(bothdo

ses)

jOrganizationof

muscle

fibersat

7and14

days

(bothdo

ses)

4050

502

,Injuredarea

at7days

(bothdo

ses)

jIm

mun

ostainingof

MyoD

at7days

(bothdo

ses)

DeAlmeida

etal.24

TA(W

istarrat)

Trauma

810

100

0.028

1035

.71

1Sing

lepoint

1hr

postinjury,

once

perday

6,12

,and

24hrs

,COX-2

andTN

F->mRNAs

at6,

12,and

24hrs

(alldo

ses)

3010

7.14

3

9032

1.43

9,Dam

ageandmorph

olog

icchangescaused

bythe

injury

(alldo

ses)

DePaiva

Carvalho

etal.37

TA(W

istarrat)

Strain

810

100

0.028

3010

7.14

3Sing

lepoint

1hr

postinjury,

once

perday

3and6hrs

,COX-1

andCOX-2

mRNA

at3and6hrs

,Plasmalevelsof

PGE2

at3and6hrs

,SF

Iat

6hrs

Vatansever

etal.26

TA(W

istarrat)

Cryoinjury

830

300.0028

2930

0.87

Sing

lepoint

24hrspostinjury,

once

perday

7days

jMyoDandVE

GFmRNAs

Assiset

al.38

TA(W

istarrat)

Cryoinjury

808

300.0078

547

180

1.4

Sing

lepoint

Immediately

postinjury,

once

perday

4days

,Lipidperoxidation

(TBAR

S)andnitrotyrosineform

ation

,Prod

uction

ofnitric

oxide

,Proteinexpression

ofiNOS,

TNF->,and

IL-1A.

,NF-JAandCOX-2

mRNAs

jSO

DmRNA

(Con

tinuedon

next

page)



various sports.3 Football (soccer) is one of the mostpracticed sports modalities in the world, and it isestimated that one-third of injuries that occur duringthe practice of this sport are muscle related.3,43 Suchinjuries often result in an inability to participate intraining and competitions, compromised athleticperformance, and an increased susceptibility to re-current injuries.1,8,9 The best treatment of muscleinjuries has not yet been clearly defined. Moreover,treatment protocols vary considerably dependingon the severity of the injury.1,44,45 Therefore, stan-dardized therapeutic approaches that can accelerateand enhance the muscle repair process are extremelyimportant.

LLLT has emerged as an option for the treat-ment of muscle injuries. This noninvasive, low-cost,easy-to-administer form of therapy can help reducethe use of medications, which are often associatedwith side effects. In contrast, no side effects havebeen reported for LLLT. In this review, all articlesreported beneficial effects of this resource in thetreatment of acute muscle injuries, such as modu-lation of the inflammatory process,22Y24,35,36,41 thestimulation of new blood vessels,22,32 remodeling ofthe ECM,22,32,33 and stimulation of the prolifera-tion and differentiation of satellite cells.26,27,35,3

Thus, the present review is of paramount impor-tance to the choice of irradiation and treatmentparameters, allowing a better understanding of themechanisms involved.

Among the articles included in this review,considerable heterogeneity was found regarding theirradiation and treatment parameters as well as themethods used to measure the results. Furthermore,the different experimental models of muscle injuryused, such as cryoinjury (n = 11), trauma (n = 3),surgical induction (n = 1), and excessive stretching(n = 2), hinder the comparison of the results be-cause of variations in the extent of different types ofinjury.46 For example, cryoinjury causes localizedmuscle damage and inflammation, with the de-struction of local vessels and nerves, resulting inpartial neurovascular injury and fibrosis at thesite.47,48 In contrast, stretching causes muscle dam-age and inflammation that can extend throughoutthe epimysium, resulting in bleeding between thefascia and themuscle,49 and often affects componentsof the myotendinous junction.50

The conservative management of muscle inju-ries is commonly accepted.8 The most often usedtherapeutic resources for conservative treatment arecryotherapy,51,52 nonsteroidal anti-inflammatorydrugs or corticosteroids,52,53 massage,54 hyperbaricoxygen therapy,55 therapeutic ultrasound,56 shockTA

BLE

2(Con

tinued)

Autho

rsMuscleand

Animal

Injury

Mod

elWavelength,

nmPow

er,

mW

Beam

Spot,cm

2

Irradiation

Tim

eper

Points,secs

Energy

Density,

J/cm

2

Total

Energyper

Treatment,J

Sing

leor

Multiple

Points

Onset

and

Frequencyof

Treatment

Periods

Evaluated

Results

Ram

oset

al.39

TA(W

istarrat)

Strain

810

100

0.028

1035.71

1Sing

lepoint

1hr

postinjury,

once

perday

6and

12hrs

Fatigu

eou

tcom

e:jPeak

force%

ofmaxim

alcontractionat

12hrs

(doseof

1and3J)

jTimeto

decrease

to50

%of

maxim

alcontractionat

6hrs(alldo

ses)

3010

7.14

3jTimeto

decrease

to50

%of

maxim

alcontraction

at12

hrs(onlywith9J)

6021

4.29

6jAU

C%

at6hrs(exceptd

oseof6J)

9032

1.43

9jAU

C%

at12

hrs(alldo

ses)

,SF

Iat

12hrs(exceptdose

of9J)

Renno

etal.40

TA(W

istarrat)

Cryoinjury

830

300.028

4750

1.41

Sing

lepoint

24hrspostinjury,

once

every

48hrs

13days

,Dam

ageandmorph

olog

icchangescaused

bytheinjury

,Im

mun

ostainingof

COX-2

Cresson

ietal.31

TA(W

istarrat)

Surgical

indu

ction

785

750.3

363

2.7

Multiple

points(3)

24hrspostinjury,

once

every

48hrs

2,4,

and

8days

,Po

lymorph

onuclear

leuk

ocytes

andmon

onuclear

cells

at2,4,

and8days

jFibrob

lastsat

8days

AUC,areaun

derthecurve;iNOS,

indu

ciblenitric

oxidesynthase;N

F-JA,n

uclear

factor

kapp

aB;S

FI,S

ciatic

Function

Index;SO

D,sup

eroxidedism

utase;TB

ARS,

thiobarbituric

acid

reactive

substances.



wave therapy, and electrical stimulation.2,3 Withregard to LLLT, the choice of irradiation andtreatment parameters, such as wavelength, poweroutput, beam area, total energy, irradiation time,frequency of treatment, mode of application, andthe onset of treatment, are crucial to achievingpositive effects in the treatment of muscle injuries.Unfortunately, few studies adequately describe allthe information essential to the reproducibility andthe reliability of the findings.57

In the present review, the main criteria that ledto the exclusion of articles were an inadequate de-scription of the beam area, which is critical to de-termining the energy delivered to the tissue, andthe nondescription of the onset of treatment afterthe induction of injury. These points are extremelyimportant to the study of the muscle repair processbecause the administration of light at differenttimes can exert an influence on each stage of therepair process by modulating different cell typesand events that have a direct effect on the results.58

This is seen clearly in the comparison of two studiesthat used the same irradiation parameters but ini-tiated treatment at different times. Baptista et al.33

began treatment 24 hrs after injury induction andfound no differences in histologic features, whereasDe Souza et al.32 initiated treatment 4 hrs afterinjury induction and found both a reduction inmyonecrosis and an increase in the number ofblood vessels after 7 days.

Another important factor observed in this sys-tematic review is that only one study correlatedthe biochemical/molecular findings with clinical/functional improvement. De Paiva Carvalho et al.37

evaluated functional recovery using the walkingtrack test outcome (sciatic function index) and foundthat LLLT (wavelength, 810 nm; power output,100 mW; total energy, 3 J) was effective in improv-ing functional recovery in association with a de-crease in inflammatory markers (cyclooxygenase-1[COX-1], COX-2, and prostaglandin E2 [PGE2])after 6 hrs. Ramos et al.39 also used the walkingtrack test outcome for functional assessment andanalyzed three parameters of muscle fatigue toevaluate muscle performance: (1) the maximumforce elicited at the onset of each of the six electri-cally induced tetanic contractions, (2) the timeelapsed until a 50% reduction in the force ofan electrically induced contraction in comparisonwith the force at the onset of contraction, and (3)muscle performance after electrically induced te-tanic contraction. The authors found that LLLT(wavelength, 810 nm; power output, 100 mW)was effective in enhancing functional recovery andTA

BLE


usedlaserin

pulsedmode

Autho

rsMuscleand

Animal

Injury

Mod

elWavelength,

nm

Power,m

W

Beam

Spot,

cm2

Irradiation

Tim

eper

Points,

secs

Energy

Density,

J/cm

2

Total

Energyper

Treatment,J

Sing

leor

Multiple

Points

Onset

and

Frequencyof

Treatment

Periods

Evaluated

Results

Pulse,n

s

Frequency,

Hz

DeAlmeida

etal.41

TA(W

istarrat)

Trauma

904

600.03

6417

27.47

1Sing

lepo

int

1hr

postinjury,

once

perday

6hrs

,Proteinexpression

ofTN

F->,IL-1A

,andIL-6

(only1-J

dose)

200

5082

.42

370

010

016

4.84

615

024

7.25

9Silveira

etal.42

Gastrocnemius

(Wistarrat)

Trauma

904

400.10

12.5

52.5

Multiple

points(5)

2hrspo

stinjury,

3times

inthe

firstday(2,12,

and24

hrs)and

each

24hrs

5days

,Serum

CKactivity

60,TB

ARSlevels

9500

,Su

peroxide

anionproductio

n,Activity

ofSO

D,Hydroxyprolinecontent

CK,creatinekinase;S

OD,sup

eroxidedism

utase;TB

ARS,

thiobarbituric

acid

reactive

substances.



muscle performance in the periods evaluated (6 and12 hrs) but did not assess biochemical/molecularmarkers. Thus, there remains a gap in the correla-tion of biochemical/molecular findings with func-tional analysis. Future studies that examine bothaspects could bring a better understanding ofthe relationship between biochemical makers andfunctional recovery, which is of considerable im-portance to the field of rehabilitation.

Effect of LLLT on InflammationThe inflammatory phase is characterized by

the degeneration of muscle fibers, the recruitmentof neutrophils and macrophages to the injury site,as well as the production of inflammatory cytokines(tumor necrosis factor alpha [TNF->], interleukin 1beta [IL-1A], IL-6, and IL-8) and proteolytic en-zymes responsible for the phagocytosis of celldendrites and the spread of the inflammatory re-sponse.2,59 This phase is also accompanied by anincrease in the production of reactive oxygen spe-cies, such as superoxide, hypochlorous acid, andhydrogen peroxide, which may also be involved inthe exacerbation of the inflammatory process,causing damage to healthy muscle fibers.60,61 Thus,LLLT in this phase may enhance the tissue repairprocess, possibly through its ability to limit theinflammatory response and attenuate oxidativedamage. Indeed, LLLT has been shown to be an ex-tremely efficient therapeutic resource for the modu-lation of the inflammatory process after muscleinjury, regardless of the characteristics of the laserdevice, such as operating mode (continuous orpulsed), type of emitter (Gallium Arsenide, Alumi-num Gallium Arsenide, and Aluminum Gallium In-dium Phosphide), and range of the light spectrum(red or infrared) (Tables 1Y3).

Furthermore, LLLT has been shown to be moreeffective than the administration of the pharmaco-logic agent diclofenac sodium, which is a potentnonsteroidal anti-inflammatory drug that acts byblocking the pathway of COX inhibitors.61 COX-1and COX-2 are the most highly expressed membersof the COX family in injured muscle.62 COX-1 playsa constitutive role and synthesizes prostaglandins,which are important to homeostasis,63 whereasCOX-2 contributes to the production of PGE2, whichis related to pain and the recruitment of inflam-matory neutrophils.64,65 De Paiva Carvalho et al.37

demonstrated that LLLT (wavelength, 810 nm; poweroutput, 100 mW; total energy, 3 J) was as effectiveas the topical and the intramuscular administrationof diclofenac sodium on the expression of COX-1

and COX-2 after 3 and 6 hrs and exhibited a bettereffect on the reduction of PGE2 and the functionalimpairment index (walking track analysis) 6 hrs afterthe induction of stretch injury. De Almeida et al.41

compared the effects of cryotherapy, the topical ap-plication of LLLT, and diclofenac sodium in an ex-perimental model of muscle injury induced by acutetrauma in rats and found that LLLT (wavelength,904 nm; power output, 60 mW; total energy, 1 J)had a better effect on the reduction of proinflamma-tory cytokines (TNF->, IL-1A, and IL-6) 6 hrs afterinduced injury in comparison with the other formsof treatment.

However, it should be noted that the stronginhibition of factors involved in inflammation, suchas proinflammatory cytokines, can be harmful tothe regeneration of tissue because these factorsstimulate proliferation and prevent the prema-ture differentiation of myogenic precursor cells.66

Nonetheless, studies using laser in the inflamma-tory phase have reported beneficial effects on therepair of muscle tissue.

Effects of LLLT on MyogenicRegulatory Factors

The activation of satellite cells occurs simul-taneously to the inflammatory process. Although asmall proportion undergoes self-renewal (i.e., a re-turn to the quiescent state to replenish the satellitecell population), most contribute to the regene-ration process and differentiate into myoblasts,which fuse to repair damaged fibers or form a newfunctional muscle fiber.5,67,68 Satellite cells expressmyogenic regulatory factors (MRFs), which are com-posed of four members: Myf5, MyoD, myogenin,and MRF4. The primary MRFs are Myf5 and MyoD,which play roles in determining myogenesis andconverting precursor cells into myoblasts. The sec-ondary MRFs (myogenin and MRF4) are importantto cell differentiation into myoblasts and myocytesfor the formation of mature muscle fibers.68 Thus,the modulation of MRFs can directly influence themuscle repair process. Recently, LLLT has shownpromise in modulating MRFs regardless of the irra-diation or treatment parameters.

Rodrigues et al.35 report an increase in theexpression of MyoD messenger RNA (mRNA) after7, 14, and 21 days; a reduction in the expression ofmyogenin mRNA after 7 days; and an increase inmyogenin mRNA after 21 days using red laser(wavelength, 660 nm; power output, 20 and 50 mW;total energy, 0.4 and 2 J) for the treatment of theTA muscle after cryoinjury. Using infrared laser



(wavelength, 830 nm; power output, 30 mW; totalenergy, 0.87 J), Vatansever et al.26 found an increasein the expression of MyoD mRNA after 7 days.Brunelli et al.36 found an increase in MyoD immu-nostaining after 7 days in the group treated with thelaser (wavelength, 780 nm; power output, 20 and 50mW; total energy, 0.4 and 2 J). Using LLLT (wave-length, 780 nm; power output, 30 mW; total energy,1.4 J), Assis et al.27 found increased expression ofMyoD and myogenin mRNAs after 4 days.

Although these results are extremely interest-ing, further studies should be conducted to allow abetter understanding of the effects of LLLT on themodulation of MRFs because it has been shown thatcytokines, such as TNF->, IL-1A, and IL-6, andsome growth factors, such as transforming growthfactor beta (TGF-A), fibroblast growth factor, andinsulin-like growth factorY1, can either directly orindirectly influence the proliferation and the dif-ferentiation of satellite cells.5

Effects of LLLT on ECM RemodelingECM remodeling occurs throughout the repair

process and is characterized by the synthesis andthe degradation of proteins. Initially, fibroblastsmigrate to the injury site, proliferate, and synthe-size proteins, such as collagen types I, III, and IV;laminin; fibronectin; proteoglycans; and tenascin,thereby forming a new ECM.59 The degradation ofECM proteins is mainly carried out by matrixmetalloproteinases (MMPs), which selectively digestindividual components of the ECM.69,70 In skeletalmuscle, the collagenases MMP-1, MMP-8, MMP-13,and MMP-18 have the ability to degrade interstitialcollagen types I, II, and III, and the gelatinasesMMP-2 and MMP-9 degrade denatured collagentypes IV, VII, and X in many tissues.70

Gelatinases play important roles in musclerepair because the degradation of proteins thatconstitute the basement membrane facilitates themigration, the proliferation, and the fusion ofmyoblasts as well as the formation of new bloodvessels.70,71 However, the excessive accumulation ofECM proteins in muscle tissue leads to the devel-opment of the fibrous scar tissue.72 The mechanicalbarrier created by the formation of fibrous scartissue in skeletal muscle during the regenera-tion process hampers cell migration/fusion andlimits vascular reperfusion, thereby contributing toslower tissue as well as a greater susceptibility tofurther muscle.59,70,73

The literature shows that the overproductionof TGF-A is a major factor that leads to the forma-

tion of fibrous tissue during the regeneration ofmuscle tissue in both animals and humans.74,75

TGF-A plays a key role in the initiation of fibroticcascades and the differentiation of satellite cellsinto myofibroblasts in injured muscle.76 Moreover,TGF-A regulates the production of enzymes thatdegrade ECM components, such as collagenases andgelatinases, as well as the synthesis of enzymes thatinhibit the degradation of ECM, such as tissue in-hibitors of metalloproteinases and plasminogenactivator inhibitorY1.59,77

Antifibrotic agents, such as suramin,78,79

decorin,80 and interferon gamma,81 have been usedto minimize the effects of TGF-A on the formationof fibrous tissue during the regeneration of skeletalmuscle. However, some of these antifibrotic agentshave severe side effects, which raises questionsregarding the actual benefits of clinical use inhumans.82 LLLT has been shown to be effective inmodulating the formation of fibrotic tissue duringthe repair of injured muscle tissue. Regardless ofthe irradiation and treatment parameters, LLLT hasbeen shown to be effective in reducing the geneexpression of TGF-A. Mesquita-Ferrari et al.25

used red laser (wavelength, 660 nm; power output,20 mW; total energy, 1.6 J) and found a reduction inthe expression of TGF-A mRNA after 7 days. Assiset al.27 found a reduction in the expression ofTGF-A mRNA after 4 days using infrared laser(wavelength, 808 nm; power output, 30 mW; totalenergy, 1.4 J) on the TA muscle of rats in therepair process after cryoinjury.

In contrast, collagen deposition in muscle tis-sue has been shown to be dependent on irradiationand treatment parameters. De Souza et al.32 andBaptista et al.33 used LLLT in the red spectral range(wavelength, 660 nm; power output, 20 mW; totalenergy, 1.6 J) and found increased immunostainingof collagen types I, III, and IV after 7 days in theTA muscle of rats during the repair process aftercryoinjury. Assis et al.27 used infrared laser (wave-length, 808 nm; power output, 30 mW; total energy,1.4 J) and found a reduction in the deposition oftype I collagen after 4 days. Alves et al.22 also usedan infrared laser (wavelength, 780 nm; power out-put, 40 mW; total energy, 3.2 J) on the same ex-perimental model and found an increase in thegelatinolytic activity of MMP-2 associated with animprovement in the organization and distributionof collagen fibers.

These findings demonstrate that the choiceof irradiation parameters is crucial to achievingthe desired effects during treatment with LLLT.However, the effects of LLLT on other growth



factors, such as connective tissue growth factor,platelet-derived growth factor, and myostatin,which are directly related to the development offibrosis in muscle tissue, have not been studied.59

Effects of LLLT on AngiogenesisThe development of a new network of blood

vessels (angiogenesis) at the injury site is extremelyimportant to successful muscle regeneration. Thisprocess is regulated by vascular endothelial growthfactor (VEGF), which exerts different effects on thevascular endothelium, including endothelial cellproliferation, the induction of rapid microvascularpermeability, the survival of endothelial cells, themigration and adhesion of endothelial cells, andsubsequent fusion between new vessels with pre-existing movement.83,84 Furthermore, it has beendemonstrated that VEGF stimulates the expansionof the number of basal satellite cells adjacent tonew capillaries, mainly because satellite cells residein a juxtavascular niche. These findings demon-strate the dual (proangiogenic and promyogenic)functionality of VEGF.85

The results of the present review clearly showthat LLLT is extremely effective in modulating theexpression of VEGF mRNA and the consequentformation of new blood vessels during the repair ofinjured skeletal muscle. Rodrigues et al.35 reportthat LLLT (wavelength, 660 nm; power output,20 and 50 mW; total energy; 0.4 and 2 J) promoteda reduction in the expression of VEGF mRNA after7 days and an increase after 14 and 21 days in theTA muscle during the repair process after cryo-injury. Vatansever et al.26 found an increase in theexpression of VEGF mRNA after 7 days using in-frared laser (wavelength, 830 nm; power output,30 mW; total energy, 0.87 J). Also using infraredlaser (wavelength, 808 nm; power output, 30 mW;total energy, 1.4 J), Assis et al.27 found an increasein the expression of VEGF mRNA after 4 days. Alveset al.22 and De Souza et al.32 demonstrated an in-crease in the number of blood vessels after 7 daysusing the same experimental model but differentirradiation parameters.

It is noteworthy that some of these studies alsofound an increase in the expression of MyoD andmyogenin mRNA associated with the increase inVEGF. These MRFs are commonly used as markersof satellite cell proliferation and differentiation.

CONCLUSIONSThe studies analyzed demonstrate the posi-

tive effects of LLLT on the muscle repair process,

which are dependent on irradiation and treatmentparameters. The findings suggest that LLLT is anexcellent therapeutic resource for the treatment ofskeletal muscle injuries in the short-term. However,the biologic mechanisms of action of LLLT have notyet been fully clarified, and further investigationshould be conducted involving animal models andrandomized human clinical trials.

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