Effect of tenotomy on metabosensitive afferent fibers from tibialis anterior muscle

Exp Brain Res

RESEARCH ARTICLE

EVect of tenotomy on metabosensitive aVerent Wbers from tibialis anterior muscle

Jérôme Laurin · Julien Gondin · Erick Dousset · Patrick Decherchi

Received: 16 August 2007 / Accepted: 5 November 2007© Springer-Verlag 2007

Abstract In previous studies, the eVect of tenotomy hadbeen focused mainly on muscle properties (typology, capil-larity, force, etc.). Little attention was paid to the metabo-sensitive Wbers from groups III and IV (also called‘ergoreceptors’ or ‘exercise receptors’). In the currentstudy, we assessed the metabosensitive responses in a ratmodel with tenotomized muscle. Two groups of animalswere included: a control group (C, no tenotomy) and atenotomized group (Tn, transection of the distal tendon ofthe left tibialis anterior). After 10 weeks, we observed inthe Tn group a signiWcant decrease in the metabosensitiveaVerent responses to electrically induced fatigue and tochemical agents (KCl and lactic acid), known to activatethe metabosensitive Wbers. These data indicate that (1)tenotomy induces an alteration in the metabosensitiveresponse and consequently modiWes the sensory–motorloop; (2) metabosensitive Wbers may have a secondary rolein tenotomy-induced muscle properties alterations. Addi-tional studies are required to improve our understanding ofthe metabosensitive responses after tendon or nerve injury.

Keywords Electrophysiology · Tendon injury · Group III and IV

Introduction

Tenotomy can result from trauma such as rotator cuV rup-ture, Achilles tendon injury and tendon laceration. Surgicalmanipulation-induced tenotomy have numerous clinicalimplications in the treatment of degenerative musculoskele-tal diseases and rheumatologic diseases such as arthropathy(Jamali et al. 2000). It has clearly been established thattenotomy results in decreased muscle mass (Eccles 1944)and force generation capacity (Buller and Lewis 1965) aswell as in muscle Wber disorganization and sarcomereshortening (Abrams et al. 2000; Jamali et al. 2000). Like-wise, Jozsa et al. (1990) demonstrated that the capillarydensity was markedly decreased 3 weeks after tenotomy ofboth soleus and gastrocnemius muscles. Interestingly,4 weeks of recovery led to a rapid adjustment of the sarco-mere length to normal values (Baker and Hall-Craggs1978). However, several investigations reported that suchchanges occurring at the muscle level could be reduced byboth denervation and spinal cord lesion (McMinn and Vrb-ova 1964, 1967; McLachlan 1983a, 1983b; McLachlan andChua 1983). When tenotomy was associated with a nervesection, muscle atrophy and reduction of muscle Wberlength were decreased, while the restoration of the sarco-mere length occurred at a slower rate (McLachlan 1983a,1983b; McLachlan and Chua 1983). It was therefore sug-gested that the nervous system, especially muscle aVerentpathways, was involved in the atrophic and deleteriouseVects of tenotomy (Jamali et al. 2000). Nevertheless, fewstudies investigated the inXuence of tenotomy on muscleaVerent Wbers. Furthermore, the results are controversial.For example, Kawano et al. (2004) recently showed thattenotomy of soleus and surrounding muscles induced adecrease in the activity level of aVerent neurogramrecorded on the dorsal root from the soleus muscle. In

Jérôme Laurin and Julien Gondin contributed equally to this work.

J. Laurin · J. Gondin · E. Dousset · P. Decherchi (&)Laboratoire des Déterminants Physiologiques de l’Activité Physique (UPRES EA 3285), Parc ScientiWque et Technologique de Marseille-Luminy, Institut des Sciences du Mouvement: Etienne-Jules MAREY (IFR107), Faculté des Sciences du Sport de Marseille-Luminy, Université de la Méditerranée (Aix-Marseille II), Case Postale 910, 163, avenue de Luminy, 13288 Marseille Cedex 09, Francee-mail: patrick.decherchi@univmed.frURL: www.physiologie.staps.univ-mrs.fr

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contrast, Kozak and Westerman (1961) observed a signiW-cant increase in aVerent discharges from chronically teno-tomized cat muscles. These discrepancies could beascribed, at least in part, to the type of aVerent Wbersrecorded and the stimuli chosen since each group of Wbersis activated by speciWc stimuli (Gandevia 2001). Thus, therole of aVerent pathways in the degenerative eVects oftenotomy need to be determined more precisely.

Among the aVerent Wbers, myelinated group III andunmyelinated group IV Wbers act primarily as mechano-and metabosensitive nerve endings, respectively. They arecalled muscle ‘ergoreceptors’ or ‘exercise receptors’because they detect changes in the metabolism of muscleexercise (Rotto and Kaufman 1988) and in intramuscularpressure (Ge and Khalsa 2003). They are selectively acti-vated during and after muscle fatigue (Decherchi et al.1998, 2001; Dousset et al. 2001) or by diVerent agents suchas bradykinin (Kaufman et al. 1982), lactic acid (Rotto andKaufman 1988; Marqueste et al. 2002), arachidonic acid(Rotto and Kaufman 1988), thromboxane A2 (Kenagy et al.1997), H+ (Victor et al. 1988), prostaglandin (Rotto andKaufman 1988) and potassium chloride (Rybicki et al.1985; Decherchi et al. 2001; Dousset et al. 2001; Marque-ste et al. 2002). Several studies also reported that the sensi-tivity of group III and IV aVerent Wbers was depressed afternerve repair by self-anastomosis (Decherchi et al. 2001;Marqueste et al. 2002). Because these aVerent Wbers origi-nate from both muscles and tendons, it can be hypothesizedthat tenotomy aVects the activation of the group III and IVaVerent Wbers.

The purpose of the present rat study was to measure theeVect of a chronic tenotomy on the response of the tibialisanterior group III and IV aVerent Wbers. The metabosensi-tive aVerent discharges were recorded after direct electricalmuscle stimulation and intra-arterial injections of potas-sium chloride or lactic acid.

Materials and methods

Six-month-old male Lewis rats, weighing 500 g (CharlesRiver®, Les Oncins, France), were housed in smooth-bot-tomed plastic cages at 22°C with a 12 h light/dark cycle.Food (Purina®, rat chow) and water were available ad libi-tum. Anesthesia and surgical procedures were performedaccording to the French law on animal care guidelines andthe Animal Care Committee of University Aix-Marseille IIapproved our protocols. Furthermore, experiments havebeen carried out in accordance with the European Commu-nity’s council directive of 24 November 1986 (86/609/EEC). Analgesic drugs (Finadyne®, 5 mg/kg) were admin-istered to minimize pain or discomfort. No clinical sign ofpain sensation (i.e., screech, prostration, hyperactivity,

anorexia) and no paw-eating behavior were observedthrough the experiment.

Rats (n = 12) were randomized into two groups: (1) con-trol group (C, n = 6) without any surgery, (2) tenotomizedgroup (Tn, n = 6) in which a tendon from the hind limb wastransected. In this last group, the animals were anesthetized(chloral hydrate, Sigma®, 60 mg/kg) and using an operatingmicroscope (£40, OPM 11 Zeiss, Oberkochen, Germany),a 2 cm skin incision was made at the ankle level underaseptic conditions. A length of 1–2 mm of the distal tendonof the left tibialis anterior muscle was dissected free fromsurrounding tissues and transected with small scissors closeto the bone point insertion. Blood and nerve supplies werekept intact. A shortening of the tibialis anterior muscle wasobserved immediately after tenotomy. Skin incision wasthen sutured (Flexocrin® 3–0, B. Braun) and the animalswere allowed to recover in individual cages.

Ten weeks post-tenotomy, the rats were re-anesthetizedby an intra-peritoneal injection of solution containingsodium pentobarbital (Nembutal®, SanoW Santé Animal,60 mg/kg). A tracheotomy was performed and rats wereartiWcially ventilated (Harvard® volumetric pump: rate 40–60 min¡1, tidal volume 2–4 ml; Southmatick, MA, USA).A catheter was inserted into the right femoral artery andpushed up to the fork of the abdominal aorta in order totransport the chemicals [i.e., potassium chloride (KCl) andlactic acid (LA)] to the contralateral muscle. This catheterwas positioned in order to let the blood Xow freely to themuscles of the left lower limb. The knee and ankle wereWrmly held by clamps on a horizontal support in order toavoid limb motion during electrical muscle stimulations. Asteel hook was implanted in the tibialis anterior muscle andconnected to a strain gauge (Microdynamometer S 60; UgoBasile Narco Biosystem) to measure isometric force. Theleft peroneal nerve was dissected free from surrounding tis-sues on a length of 3–4 cm and its proximal portion was cutout. In order to record the aVerent activity at the tibialisanterior muscle, the free end of the distal nerve wasdivided into several Wlament bundles using an operatingmicroscope (£40, MZ75®, Leica, Heerbrugg, Switzerland).Each bundle was positioned on a monopolar tungsten elec-trode and immersed in paraYn oil. The nerve activity wasreferred to a ground electrode implanted in a nearby muscleand ampliWed (50 to 100 K) and Wltered (30 Hz to 10 kHz)with a diVerential ampliWer (P2MP® SARL, Marseille,France). The aVerent discharge was recorded (BiopacMP150® and AcqKnowledge® software) and fed into pulsewindow discriminators (P2MP® SARL, Marseille, France),which simultaneously analyzed aVerent populations. Theoutput of these discriminators provided noise-free tracings(discriminated units), which were counted using data analy-sis system (Biopac AcqKnowledge® software) at 1 s inter-vals (in Hz) and then displayed on a computer. The

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discriminated units were counted and recorded on separatetracings. Due to the small size of action potentials of thethin aVerent Wbers in each bundle, the window discrimina-tors allowed us to select 1 or 2 units in each aVerent popula-tion (i.e., 2–4 units per Wlament bundle) and to studyactivities of the aVerent populations. More details of therecording protocol may be found in our previous studies(Decherchi et al. 1998, 2001; Dousset et al. 2001; Marque-ste et al. 2002).

As previously described (Decherchi et al. 1998, 2001;Dousset et al. 2001; Marqueste et al. 2002), the followingtests were performed for each selected Wlament bundle: (1)response of aVerents after a 3 min low frequency (10 Hz)electrical stimulation of the tibialis anterior muscle (simu-lated fatigue). Such electrically induced muscle fatigue(EIF) was elicited by a neurostimulator (Grass S8800) thatdelivered, through an isolation unit, rectangular pulse trainsto a pair of steel hooks implanted in the muscle (pulse dura-tion: 0.1 ms; 10 Hz, i.e., Wve shocks in 500 ms train; dutycycle: 500/1,500 ms). The voltage was supramaximal, i.e.,25% higher than that used to elicit a twitch. Fatigue wasassessed from the decay in force throughout the 3 min EIFperiod. The discharge rate of nerve aVerents was averagedfor a 1 min period preceding EIF, and its maximal changewas measured during the Wrst 2 min period following EIF.(2) response of aVerent units to intra-arterial bolus injectionof KCl (1, 5, 10 and 20 mM in 0.5 ml saline) or LA solu-tions (0.5, 1, 2 and 3 mM in 0.1 ml saline). There was a15 min delay between each injection in order to let theaVerent activity go back to its baseline. At the end of theexperiment, the rats were killed by an intra-arterial pento-barbital overdose.

AVerent Wber baseline discharge (Fimpulses s¡1) was aver-aged at time zero, irrespective of the stimulus applied later.SigniWcant changes in aVerent activity induced by each testagent were determined with respect to the correspondingaveraged baseline value. Frequencies are given asmean § SEM and calculated from the measured raw val-ues. Data processing was performed using a software pro-gram (Instat® 3.0, GraphPad software, San Diego, CA,USA). Non-parametric Wilcoxon signed rank (no gaussianassumption) one-tailed and Mann–Whitney (unpaired) two-tailed tests were used to assess signiWcant modiWcations ofthe aVerent activity. DiVerences were considered signiWcantwhen P < 0.05.

Results

The metabosensitive aVerent Wbers have a tonic low fre-quency spontaneous baseline activity (3–10 Hz) under ourexperimental conditions. Their responses consisted in anincrease in basic tonic activity within the Wrst 20 s after

application of the stimulus. The response approximatelylasted 3 min. During the recovery time, the aVerent dis-charge frequency returned to baseline values for each Wla-ment bundle.

Electrically induced fatigue (EIF)

As shown on Fig. 1, a signiWcant increase of aVerent dis-charge frequency was observed only in C group(P = 0.0313) after a 3 min stimulation of the tibialis ante-rior muscle (C = 115.9 § 9.7%). No signiWcant change wasobserved in the Tn group. When compared to C group, thetenotomized animals exhibited a signiWcant (P = 0.0152)loss of aVerent response to EIF.

Potassium chloride (KCl)

Figure 2 shows that signiWcant increases in the aVerent dis-charge frequency were observed in the C group for the fol-lowing concentrations of KCl solution used:C = 110.9 § 2.8% (5 mM, P = 0.0156), 121.2 § 3.4%(10 mM, P = 0.0156), 124.8 § 4.2% (20 mM, P = 0.0156).The aVerent Wber activation of group III and IV started at aconcentration of 1 mM and then the response plateaued.For the Tn group, a small signiWcant increase in the aVerentdischarge was observed only at a concentration of 10 mM:Tn = 104.6 § 1.9% (P = 0.0469). No signiWcant changewas observed for the other concentrations. When comparedto C group, Tn animals exhibited a loss of aVerent responseto KCl at the concentrations of 5 mM (P = 0.026), 10 mM(P = 0.043) and 20 mM (P = 0.022).

Lactic acid (LA)

Figure 3 shows that signiWcant increases in the aVerent dis-charge frequency were observed in the C group, whateverthe concentration of the LA solution used: C = 108.2 § 4.7%

Fig. 1 AVerent nerve response to Electrically Induced Fatigue (EIF).The post-EIF changes in aVerent discharge rate (Fimpulses s¡1) are onlysigniWcant in control rats (+, P < 0.05). The diVerences between teno-tomized and control rats are signiWcant (*, P < 0.05)

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(0.5 mM, P = 0.0156), 106.4 § 2.2% (1 mM, P = 0.0156),123.4 § 4.3% (2 mM, P = 0.0156), 107.7 § 2.8% (3 mM,P = 0.0156). The activation of the aVerent Wbers of groupIII and IV started at a concentration of 0.5 mM, and theresponse culminated for [2 mM]. For the Tn group, a smallsigniWcant increase in the aVerent discharge was observedonly at a concentration of 1 mM: Tn = 104.2 § 0.8%(P = 0.0156). No signiWcant change was observed for theother concentrations. When compared to C group, Tn animalsexhibited a loss of aVerent response to LA at a concentrationof 2 mM (P = 0.0022).

Discussion

The major Wnding of the present study was a signiWcantalteration of group III and IV metabosensitive Wbers in

response to speciWc stimuli (i.e., potassium, lactate, EIF)after a chronic tenotomy of the tibialis anterior muscle.

In the C group, aVerent discharge signiWcantly increasedafter KCl and LA injections. In accordance with a previousstudy (Alluin et al. 2006), the dose-dependent relationshipbetween the discharge rate and the KCl or LA concentra-tions was observed in control rats. Arterial KCl injectionsare able to increase muscle interstitial potassium concentra-tions to levels similar to those evoked by static contractionand, consequently, to activate group III and IV aVerentWbers (Thimm and Baum 1987). The amounts of LA usedin our experiments were suYcient to (1) create a hydrogenion concentration in the tibialis anterior muscle similar oreven superior to the level measured in this muscle duringhigh strength contractions and (2) cause an increase indischarge frequency of III and IV aVerent Wbers. Further-more, the relative low-frequency stimulation (EIF, 10 Hz)used in our experimental conditions induced intramuscularmetabolite accumulation (muscle acidosis induced adecline in the number of attached cross bridges and adecrease in the force exerted by each bridge). Thus, theeZux of lactate into the extracellular space during low-fre-quency stimulation is a potent activator of muscle metabo-sensitive Wbers.

In the Tn group, the response of the aVerent metabosen-sitive Wbers, after a 3 min EIF, was markedly decreased orabsent when compared to animals of the C group. Metabolitesreleased by the working muscle in the Tn group afterelectrical stimulation or extrinsically injected metabolitesseemed to be poorly eVective. Namely, the group III and IVaVerent Wbers did not respond to the highest concentrationsof KCl and to the various doses of lactic acid, except for10 mM of KCl and 1 mM of LA. Kawano et al. (2004)reported a decrease in aVerent neurogram after tenotomy ofthe soleus and the surrounding muscles. However, the typeof aVerent Wbers recorded by these authors was not men-tioned. They recorded the whole aVerent discharge at thedorsal root of the Wfth lumbar (L5) segmental level of thespinal cord without discriminating between the mechanicaland metabolic aVerent Wbers during postural and suspen-sion positions after tenotomy. The postural position isknown to activate mainly the mechanosensitive and not themetabosensitive aVerent Wbers. In the present investigation,we showed for the Wrst time that the metabosensitive aVer-ent Wbers are also aVected by tenotomy.

Several eVects of tenotomy on muscle structures canexplain the changes observed in group III and IV aVerentmetabosensitivity. One week after a tendon retraction, areattachment to the surrounding connective tissues wasobserved (McLachlan 1983a; McLachlan and Chua 1983;Elder and Toner 1998). As a consequence, the tendontension was reduced, when compared to a non-injured one.This change in tension could alter the group III and IV

Fig. 2 AVerent nerve response to potassium chloride (KCl). Thechanges in discharge rate (Fimpulses s¡1) are measured after a stepwiseincrease in KCl concentration. Crosses indicate signiWcant changeswhen compared to the resting discharge rate (+, P < 0.05). In compar-ison to control rats, tenotomy attenuates the nerve responses to KCl atthe concentrations of 5, 10 and 20 mM (*, P < 0.05)

Potassium Chloride Injections

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Fig. 3 AVerent nerve response to lactic acid (LA). The changes in dis-charge rate (Fimpulses s¡1) are measured after a stepwise increase in LAconcentration. Crosses indicate signiWcant changes when compared tothe resting discharge rate (+, P < 0.05). In comparison to control rats,tenotomy attenuates the nerve responses to LA at the concentration of2 mM (**, P < 0.01)

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tendon aVerent excitability threshold and thus theirresponse to stimuli. The decline of the local tendon aVerentresponse could aVect the whole aVerent Wber response.Furthermore, since the muscle tension was modiWed, itcould be surmised that aVerent Wbers originating from themuscle are also aVected. Our results are in support of thishypothesis, since we obtained an altered response after anelectrical fatigue or a chemical stimulation.

Moreover, tenotomy is known to decrease intramuscularcapillary density (Jozsa et al. 1990). It is likely that theinjected and released chemicals remained out of reach ofthe tenotomized muscle, as well as of the control tibialisanterior muscle. Therefore, the stimuli failed to stimulatethe group III and IV aVerent receptors of the tenotomizedmuscle.

Furthermore, it is now well known that the slow twitchWbers (1) are more aVected by the tenotomy-induced shortterm atrophy than the fast twitch Wbers and (2) exhibit thegreatest degree of atrophy in the rat gastrocnemius andsoleus muscles (Jakubiec-Puka et al. 1992). Changes inmyotypology could be a potential cause of the observedalteration in the aVerent discharge. Since the spatial distri-bution of the group III and IV metabosensitive aVerentWbers was more important near the slow twitch Wbers thanin the vicinity of the fast twitch Wbers (Rymer 1996), wecannot exclude that tenotomy also induced changes in thedistribution of the metabosensitive aVerents Wbers originat-ing from tibialis anterior muscle and, as a consequence,limited the response to stimuli. It would be interesting toconWrm the eVect of tenotomy on the tibialis anterior mus-cle Wber typology with further investigations.

It has also been suggested that aVerent pathways couldbe involved in the degenerative eVects of tenotomy (Jamaliet al. 2000). However, the speciWc role of the diVerenttypes of aVerent Wbers in tenotomy-induced musculareVects remains unclear. McLachlan reported, in a mousemodel with aVerent transection of the tibial nerve, that theeVect of muscle atrophy was decreased and the musclelength was less diminished after soleus tenotomy(McLachlan 1983a). McLachlan and Chua also showedthat denervation following soleus tenotomy induced aslower adjustment of sarcomere length (McLachlan andChua 1983). It was suggested that this phenomenon arosemainly from the small diameter (III and IV Wbers) andencapsulated (Golgi tendinous organ, muscle spindles)aVerent feedback decrease (Yellin 1974). With regard toour results, we can postulate that tenotomy-induced eVectsmay involve changes in the metabosensitive aVerent acti-vation. The observed decrease in responses may indirectlycontribute either to a slow adjustment of sarcomere lengthor to an increase in atrophy consequences, especiallydisturbances of the contractile properties during the weeksfollowing tenotomy. The precise contribution of every

type of aVerent to the tenotomy eVects of muscle remainsunknown and warrants further investigations.

In conclusion, this study shows that the group III and IVmetabosensitive aVerent discharge rate to several speciWcstimuli was aVected by tibialis anterior tenotomy. Thepresent results are in agreement with the hypothesis thataVerent Wbers play a secondary role in the degenerativeeVects of tenotomy. It may be suggested that the eVects oftenotomy are related partially to the pattern of group III andIV aVerent metabosensitive activation.

Acknowledgments We are grateful to the La Fondation de l’Avenir,ALARME (Association Libre d’Aide à la Recherche sur la Moelle Epi-nière), Demain Debout, Combattre la Paralysie, AMDT (AssociationMéditerranéenne pour le Développement des Transplantations) and LaFondation NRJ (sous l’égide de l’Institut de France) for their Wnancialsupport and Pr François FERON for English revision. This work wasalso supported by the Université de la Méditerranée (Aix-Marseille II).

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