Could titin have a role in strain-induced injuries?

Crig Perrin*,Kzunori Nosk,Jmes Steele

aSchool of Sport,Health and Social Sciences,Southampton Solent University Ringgold Standard Institution,Southampton,SO14 0YN,UK

bSchool of Exercise and Health Sciences,Edith Cowan University,Joondalup,WA 6027,Australia

Could titin have a role in strain-induced injuries?

Craig Perrina,*,Kazunori Nosakab,James Steelea

aSchool of Sport,Health and Social Sciences,Southampton Solent University Ringgold Standard Institution,Southampton,SO14 0YN,UK

bSchool of Exercise and Health Sciences,Edith Cowan University,Joondalup,WA 6027,Australia

It has been known for some time that strain injuries occur through the excessive lengthening of a muscle.1–3However,the precise mechanism for strain injury remains elusive and has been the subject of recent debate in theJournal of Sport and Health Science,4–9but it seems sensible to consider mechanisms at the level of the muscle fiber.It was previously believed that damage was the result of non-uniform stretching of sarcomeres on the descending limb of the length–tension curve,with the weakest sarcomeres undergoing the greatest deformation and ultimately damaging the myo fibril.10This non-uniform lengthening was also believed to explain the residual force enhancement observed during lengthening contractions,as the rapid lengthening of some sarcomeres gives rise to passive tension whilst allowing the remaining sarcomeres to operate closer to their optimal length.11While it has been shown sarcomeres do lengthen non-uniformly,it does not appear to be dependent on the strength of the sarcomere.12Furthermore,the increase in sarcomere length non-uniformity after active stretching is not correlated to the residual increase in force(r=-0.309).12Although this does not disprove the notion that sarcomere lengthening is responsible for muscle damage and injury,it does contradict the idea that the weakest sarcomeres lengthen first as suggested by the sarcomere popping theory.10

An alternative explanation is the winding filament theory, which proposestitin bindsto actin upon the presence ofcalcium, in turn reducing titin’s“free length”.13Therefore,the strain placed on titin,and itsassociated contribution to force,isgreater for an absolute increase in length.In the absence of calcium (passive stretch),titin doesnotbind to actin and hasa greaterfree length.13Thus,whilstthe increased force from titin during active contractions may be usefulin an isolated eventto preventfurther lengthening,it may also accumulate muscle damage due to the excessive lengthening of the unbound or free part of titin. Furthermore,after a bout of eccentric exercise the content of titin in a myo fibril is depleted,most likely due to direct damageto titin and removal by proteolysis.14Considering that titin also helpsstabilize myosin in a sarcomere,15any damage to titin could also potentially leave myosin vulnerable to deformation and possibly injury.Indeed,ithasbeen demonstrated thatmaximally stimulated fibers require just a 30%increase in length for injury to occurwhereaspassively stretched fiberscan reach up to a 50% increase in length before injury.16

Greater fiber strain is observed in contractions initiated at longer lengths compared to those initiated at shorter lengths (p＜0.002),17which is believed to increase injury risk. However,we propose the strain placed on titin should also be considered,which might be greater in contractions initiated at shorter muscle lengths.Indeed,when the absolute lengthening is equal between groups,the stimulation of a muscle preceding lengthening results in greater reductions in peak torque after a bout of eccentric exercise(p=0.003),17which suggests greater muscle damage.In theory,the stimulation of a muscle preceding contraction would bind titin to actin earlier,placing more strain on titin during lengthening and may explain the greater muscle damage.Although further reductions in peak torque are observed in contractions initiated at longer lengths,this is likely due to the absolute muscle length also being greater.This observation also explains why peak torque during an exercise bout is larger in contractions initiated at long compared to short muscle lengths(p＞0.05).17

It has been observed that sprinters suffer injuries to the bicep femoris(BF)long head(active contraction),18whereas dancers, performing movements such as the splits,19often suffer injuries to the semimembranosus(SM)(passive contraction).20In passive conditions,the BF may have greaterextensibility,which leavesthe SMvulnerable to injury,butin active contractions,the BF may become the shortest due to the shortening of titin when titin binds to actin.Perhaps the extensibility of titin under active conditions is a risk factor for hamstring strain injuries.Indeed reduced active flexibility appears to be a risk factor for hamstring strain injuries,21which is in contrast to passive measures of flexibility.22Interestingly,the length of the muscle(fascicle length)should not differ between active and passive contractions and so a variable that is mediated by active contractions, such as titin,is likely responsible for this finding.Furthermore,itappearsthatthe isoform oftitin altersand becomesstifferwith age,resulting in larger passive tension(p＜0.05),independent of collagen.23This may be part of the reasons older athletes are more susceptible to hamstring strain injuries.24

Continuing with the speci fic case of the hamstrings, isokinetic testing of hamstring eccentric strength is a weak risk factor for injury(odds ratio=1.37;p=0.04);25yet,strength measured during the Nordic curl(an eccentric movement)is a much stronger risk factor(relative risk=2.9;p=0.01).26It would be logical to assume that isokinetic tests may be a more speci fic tests of hamstring injury risk due to the longer muscle lengths used(hip in 90° flexion and knee achieving full extension)25compared to the Nordic curl(typically 50°joint amplitude with hip in neutral);27yet this is not the case.Tests at short muscle lengths may be a measure of eccentric strength from the active component of the sarcomere,which may be more meaningful for injury prevention.At long muscle lengths, the role of structural components such as titin may increase torque production.13Future research should determine whether passive tension,for which titin is believed to be a large contributor,in the hamstrings is a risk factor for injury.In essence, strain injuries could be dependent on not only the strain experienced by the muscle but also the contraction type and the length contraction it is initiated from.

It is acknowledged this would be a complicated hypothesis to test directly with respect to occurrence of hamstring strain injuries.However,we would expect to observe greater muscle damage in the hamstrings from contractions that are initiated at shorter muscle lengths than contractions that are initiated at longer lengths,provided that the absolute lengthening of the muscle is equal.Furthermore,it would be expected that strength toward the end of the range of motion would be greater in contractions initiated at short lengths possibly due to titin’s greater contribution.

Authors’contributions

CP conceived of the idea and wrote the initial draft;JS and KN provided feedback and assisted with the completion of the manuscript.All authors have read and approved the final version of the manuscript,and agree with the order of presentation of the authors.

Competing interests

The authors declare that they have no competing interests.

1.McCully K,Faulkner J.Injury to skeletal muscle fibers of mice following lengthening contractions.J Appl Physiol1985;59:119–26.

2.Faulkner JA,Jones DA,Round JM.Injury to skeletal muscles of mice by forced lengthening during contractions.Q J Exp Physiol1989;74:661–70.

3.Van Hooren B,Bosch F.Is there really an eccentric action of the hamstrings during the swing phase of high-speed running?Part I: a critical review of the literature.J Sports Sci2016;doi:10.1080/ 02640414.2016.1266018.[Epub ahead of print].

4.Herzog W.Eccentricvs.concentric muscle contraction:thatisthe question.J Sport Health Sci2017;6:128–9.

5.Yu B,Hu L,Garrett WE.Mechanism of hamstring muscle strain injury in sprinting.J Sport Health Sci2017;6:130–2.

6.Liu Y,Sun Y,Zhu W,Yu J.The late swing and early stance of sprinting are most hazardous for hamstring injuries.J Sport Health Sci2017;6:133–6.

7.Yu B,Hu L,Garrett WE.Comment on“The late swing and early stance of sprinting are most hazardous for hamstring injuries”by Liu et al.J Sport Health Sci2017;6:137–8.

8.Liu Y,Sun Y,Zhu W,Yu J.Comments to“Mechanism of hamstring muscle strain injury in sprinting”by Yu et al.J Sport Health Sci2017;6:139–40.

9.Li L,Wang D.Parallel and cross sectional hamstring injuries in sprint running.J Sport Health Sci2017;6:141–2.

10.Morgan DL,Proske U.Popping sarcomere hypothesis explains stretch induced muscle damage.Clin Exp Pharmacol Physiol2004;31:541–5.

11.Morgan DL.New insights into the behaviour of muscle during active lengthening.Biophys J1990;57:209–21.

12.Johnston K,Jinha A,Herzog W.The role of sarcomere length non-uniformities in residual force enhancement of skeletal muscle myo fibrils.R Soc Open Sci2016;3:150657.http://dx.doi.org/10.1098/ rsos.150657

13.Leonard TR,Herzog W.Regulation of muscle force in the absence of actin-myosin-based cross-bridge interaction.Am J Physiol Cell Physiol2010;299:C14–20.

14.Trappe TA,Carrithers JA,White F,Lambert CP,Evans WJ,Dennis RA. Titin and nebulin content in human skeletal muscle following eccentric resistance exercise.Muscle Nerve2002;25:289–92.

15.Herzog W.The role of titin in eccentric muscle contraction.J Exp Biol2014;217:2825–33.

16.Brooks SV,Zebra E,Faulkner JA.Injury to muscle fibres after single stretches of passive and maximally stimulated muscles in mice.J Physiol1995;488:459–69.

17.Butter field TA,Herzog W.Effect of altering starting length and activation timing of muscle on fiber strain and muscle damage.J Appl Physiol2006;100:1489–98.

18.Askling CM,Tengvar M,Saartok T,Thorstensson A.Acute first-time hamstring strains during high-speed running:a longitudinal study including clinical and magnetic resonance imaging findings.Am J Sports Med2007;35:197–206.

19.Askling C,Saartok T,Thorstensson A.Type of acute hamstring strain affects flexibility,strength,and time to return to pre-injury level.Br J Sports Med2006;40:40–4.

20.Askling CM,Tengvar M,Saartok T,Thorstensson A.Acute first-time hamstring strains during slow-speed stretching:clinical,magnetic resonance imaging,and recovery characteristics.Am J Sports Med2007;35:1716–24.

21.Henderson G,Barnes CA,Portas MD.Factors associated with increased propensity for hamstring injury in English Premier League soccer players.J Sci Med Sport2010;13:397–402.

22.Yeung SS,Suen AM,Yeung EW.A prospective cohort study of hamstring injuries in competitive sprinters:preseason muscle imbalance as a possible risk factor.Br J Sports Med2009;43:589–94.

23.Ottenheijm CA,Knottnerus AM,Buck D,Luo X,Greer K,Hoying A,et al. Tuning passive mechanics through differential splicing of titin during skeletal muscle development.Biophys J2009;97:2277–86.

24.Gabbe BJ,Finch CF,Bennell KL,Wajswelner H.Risk factors for hamstring injuries in community levelAustralian football.Br J Sports Med2005;39:106–10.

25.van Dyk N,Bahr R,Whiteley R,Tol JL,Kumar BD,Hamilton B,et al. Hamstring and quadriceps isokinetic strength de ficits are weak risk factors for hamstring strain injuries:a 4-year cohort study.Am J Sports Med2016;44:1789–95.

26.Timmins R,Bourne M,Shield A,Williams M,Opar D.Strength and architectural risk factors for hamstring strain injury in elite Australian soccer:a prospective cohort study.Br J Sports Med2015;50:1524–35.

27.Ditroilo M,De Vito G,Delahunt E.Kinematic and electromyographic analysis of the Nordic hamstring exercise.J Electromyogr Kinesiol2013;23:1111–8.

21 February 2017;accepted 27 February 2017

Available online 9 March 2017

Peer review under responsibility of Shanghai University of Sport.

*Corresponding author.

E-mail address:0perrc41@solent.ac.uk(C.Perrin)

http://dx.doi.org/10.1016/j.jshs.2017.03.003

2095-2546/?2017 Production and hosting by Elsevier B.V.on behalf of Shanghai University of Sport.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).