Factors predicting quadriceps femoris muscle atrophy during the first

The Knee 24 (2017) 319–328

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The Knee

Factors predicting quadriceps femoris muscle atrophy during the first 12 weeks following anterior cruciate ligament reconstruction T. Grapar Žargi a, Matej Drobnič b, Renata Vauhnik a, Jadran Koder c, Alan Kacin a,⁎ a b c

Department of Physiotherapy, Faculty of Health Sciences, University of Ljubljana, Slovenia Department of Orthopaedic Surgery, University Medical Centre Ljubljana, Slovenia Department of Radiology, University Medical Centre Ljubljana, Slovenia

a r t i c l e

i n f o

Article history: Received 2 May 2016 Received in revised form 20 September 2016 Accepted 4 November 2016 Keywords: Quadriceps muscle atrophy Muscle endurance Semitendinosus–gracilis autograft Joint swelling Knee extension ROM Volitional muscle activation

a b s t r a c t Background: Factors predicting quadriceps femoris muscle (QF) atrophy during the early period after arthroscopic ACL reconstruction have not been extensively studied. It is also yet to be confirmed whether muscle atrophy is a key determinant of postoperative QF weakness. Methods: Mean changes in QF volume, MVIC torque and isometric endurance time were analysed in 25 patients prior to and at four and 12 weeks after surgery. A multivariable regression model of change in QF volume was made from combination of several parameters of preoperative QF size and strength and postoperative joint recovery. The impact of QF atrophy on muscle weakness was evaluated with univariate regression and MVIC torque to volume ratio at postoperative week only. Results: The model of QF volume change was significant (P b 0.01) only at postoperative week 4, explaining 57% of its variation, where isometric endurance time had a negative and knee extension ROM deficit a positive weight. Change in QF volume explained (P b 0.05) 46% of the MVIC torque variation at postoperative week 12. A significant change (P b 0.05) in QF MVIC torque to volume ratio was observed at postoperative week 12. Conclusions: Good prediction of QF atrophy in the first postoperative month can be made from studied variables, with isometric endurance and knee extension ROM deficit being the most significant contributors. The atrophy explained a large part of QF muscle weakness, whereas factors contributing to the remaining portion need further research. © 2016 Elsevier B.V. All rights reserved.

1. Introduction Quadriceps femoris muscle (QF) weakness is predictive of poor knee function after injury or surgery [1]. Strength deficits equal to or more than 30% have been reported in the involved limb (OP leg) at six months after anterior cruciate ligament (ACL) reconstruction [2], at which point most patients return to full activity. QF strength deficit is prevalent regardless of ACL graft type [3] and can persist for more than two years after surgery [4,5].

⁎ Corresponding author at: Department of Physiotherapy, Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, SI-1000 Ljubljana, Slovenia. E-mail address: [email protected] (A. Kacin).

http://dx.doi.org/10.1016/j.knee.2016.11.003 0968-0160/© 2016 Elsevier B.V. All rights reserved.

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T. Grapar Žargi et al. / The Knee 24 (2017) 319–328

Preconditioning of the QF with exercise has been advocated in recent years as a means for attenuating deconditioning of knee muscles and thus augmenting functional recovery of patients after ACL reconstruction [6]. Strengthening exercise programmes have been demonstrated that increase QF strength and knee function in the injured knee of ACL-deficient patients [7,8]. However, the evidence regarding the ability of exercise preconditioning to attenuate postoperative QF atrophy and weakness in patients with ACL is conflicting. It remains unclear whether exercise preconditioning can achieve a prophylactic effect on QF size and strength, and which components of muscle performance and function are key for achieving this prophylactic effect [9–12]. The contradictory findings from these studies, with regard to postoperative QF atrophy and weakness, may be the result of known confounding factors such as different types and volume of exercise, or large intersubject variability in QF mass and strength changes. Apart from reduction of mechanical stimuli due to limb unloading and reduced whole-body activity, arthrogenic muscle inhibition (AMI) driven by pain, inflammation and swelling [13,14], as well as damage of joint proprioceptors [15–17], has been shown to contribute to the development of postoperative QF atrophy and weakness. Although it is known that QF deconditioning is most common in the first six to 12 weeks post-ACL reconstruction [18,19], the relative contribution of preoperative muscle mass and strength and rate of postoperative joint recovery to the development of QF deconditioning remains unknown. Arthrogenic muscle inhibition is regarded as the main mechanism by which long-term deficits in QF strength occur after ACL reconstruction [17,20,21]. This can affect the volitional activation of the QF bilaterally [22–25]. However, this paradigm has recently been challenged with evidence that postoperative QF strength deficit can be well explained by muscle atrophy alone; whilst the contribution of AMI to postoperative QF strength deficit remains inconsistent [3,25]. The principal aim of the present study was to investigate factors most strongly associated with QF volume loss, which would allow for early identification of patients with the highest risk of atrophy during the initial recovery phase following ACL reconstruction and thus allow for more effective individualization of preoperative training programmes. Our first hypothesis was that good prediction of postoperative QF loss can be made from a combination of parameters from the preoperative period, such as muscle status (initial atrophy, strength and endurance), and from the postoperative period, such as knee joint effusion and knee extension range of movement (ROM) deficit. The second hypothesis was that muscle atrophy alone would be predictive of postoperative QF weakness. 2. Material and methods This study was a prospective, single-centre, observational study. The study protocol was approved by the Republic of Slovenia National Medical Ethics Committee (No. 62/05/12). 2.1. Subjects Subjects were recruited from patients scheduled for an arthroscopic ACL reconstruction at the Department of Orthopaedic Surgery of the University Medical Centre of Ljubljana. Patients meeting the inclusion criteria were invited to participate and gave their written informed consent prior to inclusion. The inclusion criteria were: chronic ACL tear older than six months, patients' age from 18 to 45 years, knee pain intensity during flexion/extension activity ≤ 2.0 cm on a 10 cm visual analogue scale, and no previous surgical procedures on the affected knee. The exclusion criteria were: severe injury to the articular cartilage, gross functional impairment or severe spine or other lower-limb injuries, history of cardiovascular, respiratory or metabolic diseases and ferromagnetic implants. From April 2013 to March 2015, 62 patients (44 males and 18 females) were assessed for eligibility to enter the study. Twenty-nine patients (22 males and seven females) met the inclusion criteria and were recruited to the study, of which two subsequently decided to postpone surgery and two were excluded from the study cohort due to unplanned cartilage repair or meniscal suture performed during the ACL surgery, which substantially altered their postoperative rehabilitation protocols. Of 25 patients (20 males and five females, age = 33.5 ± 8.6 years (mean ± standard deviation), body mass index = 24.4 ± 3.6 kg/m2) who completed the study protocol, 13 also received partial meniscectomy of one (n = 12) or both (n = 1) menisci during the ACL reconstruction surgery. Given that meniscectomy did not require modification of the postoperative rehabilitation protocol, all 25 patients were included in the final analyses (Figure 1). 2.2. Sample size estimation Estimation of minimal sample size for testing difference in means with two-way analysis of variance (ANOVA) at a statistical power level of ≥0.80 (β-error ≤ 20%) was calculated based on standardized effective size for the main variable of QF volume with standard deviation (SD) = 370 cm3, acquired from our pilot experiment performed in six patients with the same methodology. By assuming a 10% change in QF volume for each factor and their interaction, the estimated minimal number of subjects was 21. 2.3. Surgical procedures and rehabilitation All subjects underwent ACL reconstruction performed by one of three experienced orthopaedic surgeons at the same institution under spinal anaesthesia. A thigh tourniquet inflated to an initial level of 300 mm Hg was used during surgery. An arthroscopic single-bundle ACL reconstruction was performed using a double-stranded ipsilateral semitendinosus–gracilis (STG) autograft. Femoral fixation was achieved by a suspensory device (ACL-TightRope, Arthrex, Naples, FL, USA). Tibial fixation was


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Figure 1. CONSORT flowchart of patient inclusion in the study. ACL, anterior cruciate ligament.

secured by an absorbable interference screw (Megafix, Karl-Storz Endoskope, Germany). The subjects started their postoperative rehabilitation on the first day post-surgery, when they were allowed to ambulate with full weight-bearing. All subjects followed the same postoperative protocol at the same outpatient physiotherapy facility three times per week during the first five weeks, followed by a 14 day intensified rehabilitation programme in a spa-based rehabilitation centre. 2.4. Study protocol overview The initial muscle size and muscle performance of both OP leg and uninvolved leg (C leg) were evaluated seven days prior to surgery. We measured QF volume and maximal voluntary isometric contraction (MVIC) torque (MVIC torque test) and time of sustained submaximal isometric contraction at 30% of preoperative MVIC torque (isometric endurance test) of the knee extensor muscles. An indirect measure of QF motor unit activation level was made by calculating the ratio between MVIC torque and muscle volume (expressed in Nm/cm3) [22]. The measurements of QF volume and isometric endurance were repeated at postoperative week 4 and postoperative week 12. To limit postoperative maximal loading of the ACL graft, the MVIC torque test was repeated at postoperative week 12 only. All subjects were familiarized with the two performance tests on two separate occasions three days prior to the initial data collection. 2.5. Muscle volume QF muscle volume was measured by magnetic resonance imaging (MRI). Proton-weighted axial scans of the right and left quadriceps muscle were acquired along the entire length of the femur using a three tesla MRI scanner (Siemens Magnetom Trio Tim, version Syngo MR B17, Germany). The maximal field of view of 292 × 420 mm and 10 mm of slice thickness with 15 mm interslice gap were used, with an echo time of 35 ms and a relaxation time of 2630 ms. The common cross-sectional area of vastus lateralis, vastus intermedius, vastus medialis, and rectus femoris, was manually tracked by one skilled musculoskeletal radiologist utilizing OsiriX 6.0 (Pixmeo SARL, Bernex, Switzerland). An overall QF volume was calculated from all acquired

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cross-sectional areas with the same software, respectively. The standard error of measurement for muscle volumes for the given researcher was 4.83 cm3 (0.28%). Percentage deficit in QF volume of the OP leg was calculated as (OP leg value − C leg value) ∕ C leg value × 100. Percentage QF volume loss after surgery was calculated as (preoperative value − postoperative value (week 4 or week 12) ∕ preoperative value × 100). 2.6. Muscle strength and endurance Subjects underwent MVIC torque measurement on a dynamometer (Isometric Knee Dynamometer, S2P d.o.o., Ljubljana, Slovenia) in a sitting position with 85° of hip flexion and 60° of knee flexion. Three four second attempts were performed with three minutes of rest between attempts in order to minimize muscle fatigue [26]. Visual feedback on a monitor and strong verbal encouragement were given to motivate the subjects. The highest mean torque over a one second period from the three attempts was calculated and used for further analyses. Relative QF strength expressed as MVIC torque normalized to body weight (MVICn torque) was used for the multiple regression model of QF volume loss. After a 20 min rest, subjects were repositioned on the knee dynamometer to perform a submaximal isometric knee-extension endurance test at 30% of their preoperative MVIC torque. A monitor was positioned in front of the subjects during the test in order to provide visual feedback of the torque output trace. Subjects were instructed to trace the 30% MVIC torque value marked on the monitor until volitional failure. If the torque output was reduced below 85% of the set value, the test was terminated by the tester prior to volitional failure. The order of tests for OP leg and C leg was randomized between subjects in a counterbalanced manner. 2.7. Muscle torque to volume ratio Volitional activation of the QF was evaluated by calculating the pre- and postoperative MVIC torque to muscle volume ratio for both the OP leg and the C leg. To calculate QF torque to volume ratio, the MVIC torque (Nm) was divided by muscle volume (cm3). This parameter has been consistently used as an indirect index of changes in voluntary recruitment of motor units and thus neural QF inhibition in both ACL-deficient and ACL-reconstructed subjects [20–22,27]. 2.8. Joint range of motion and circumference Passive knee joint extension ROM was measured using a large universal goniometer with the subject in the supine position. Full knee extension was regarded as 0° and hyperextension beyond this point as a negative value. Deficit in knee extension ROM of the OP leg was expressed as the difference between the OP leg and the C leg. This value was used for correlation analyses. Goniometric measurement variability of ±5° is generally accepted in the clinical setting [28]. Knee joint effusion was evaluated by measurement of mid-patellar girth with a standard tape measure (tape width = 8 mm) [29]. Change between preoperative and postoperative knee girth of the OP leg was used as an index of postoperative joint effusion and this measurement was used for correlation analyses. The same experienced researcher performed both measurements at all times. 2.9. Statistical analyses All statistical analyses were performed with Statistica software (Version 12, StatSoft Inc., Tulsa, Oklahoma, USA). A threshold of statistical significance was set at P b 0.05 for all tests. Unless stated otherwise, all variables are expressed as means ± SD. 2.9.1. Comparison of means Normality of distribution of each data set was analysed using the Shapiro–Wilk test and where the assumptions of normality were met, parametric statistical analysis was performed. Factorial 2 × 2 (leg × time) ANOVA with repeated measures was used to compare QF volume, MVIC torque, endurance time and torque to volume ratio. Where we found a statistically significant main effect for either factor or an interaction effect, post hoc pairwise comparisons were performed using Tukey's honestly significant difference test. 2.9.2. Regression analyses The main goal of statistical analysis was to elucidate which muscle capacity and joint recovery factors are most strongly associated with QF atrophy and weakness after ACL reconstruction. For this purpose, two separate multivariable linear regression analyses were performed with percentage QF volume loss as the dependent variable at postoperative weeks 4 and 12. Three measures of preoperative muscle status (volume deficit, MVICn torque and isometric endurance time) and two measures of postoperative joint recovery (mid-patellar girth and knee extension ROM deficit) were simultaneously introduced to the model as independent variables. A cut-off value for acceptable collinearity between variables was set at rs = ± 0.60 and none of the variables were excluded if this condition was met. The coefficient of determination (r2), model's intercept, regression coefficient (b), standardized regression coefficient (β) and P-value were computed and reported. To assess for the relative contribution of muscle atrophy to the development of QF weakness observed at postoperative week 12, a univariate linear regression was performed; where Pearson's correlation coefficient (r) was calculated.


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3. Results 3.1. Postoperative change in muscle volume For the study cohort there was a 5.8 ± 4.5% preoperative deficit in QF volume. There was a significant difference in QF volume for both the leg (P = 0.019) and time (P b 0.001) factors and for their interaction (P b 0.001). A post hoc pairwise comparison showed that muscle volume of the OP leg reduced by 17.6 ± 6.1% and 11.7 ± 7.6% at postoperative weeks 4 and 12, respectively. Muscle volume of the OP leg was smaller than the C leg by 19.5 ± 7.7% and 17.4 ± 7.9% at postoperative weeks 4 and 12, respectively (Figure 2(a)).

3.2. Postoperative change in muscle strength and endurance There was a trend towards difference in MVIC torque for the leg factor (P = 0.104) and a significant difference for the time factor (P = 0.002) and their interaction (P b 0.001). The post hoc comparison revealed that QF MVIC torque of the OP leg was lower by 13.8 ± 5.1% and 20.0 ± 9.2% at postoperative week 12 compared to preoperative values and C leg, respectively (Figure 2(b)). There was no difference in endurance time for the leg factor (P = 0.278) and a significant difference for the time factor (P b 0.001) and their interaction (P b 0.001). The post hoc comparison revealed that QF endurance time of the OP leg was lower by 30.3 ± 43.1% and 38.5 ± 34.4% at postoperative week 4 compared to PRE values and the C leg, respectively (Figure 3(a)).

Figure 2. Differences in mean quadriceps femoris (QF) volume and maximal voluntary isometric contraction (MVIC) torque between involved (OP leg) and uninvolved (C leg) lower limb prior to (PRE) and at four (POST-4w) and 12 (POST-12w) weeks after anterior cruciate ligament (ACL) reconstruction. P-values shown are those for the difference between OP leg and C leg; # denotes difference from preoperative values at P b 0.001.

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Figure 3. Differences in mean quadriceps femoris (QF) isometric endurance time and QF maximal voluntary isometric contraction (MVIC) torque to volume ratio between involved (OP leg) and uninvolved (C leg) lower limb prior to (PRE) and at four (POST-4w) and 12 (POST-12w) weeks after ACL reconstruction. P-values shown are those for the difference between OP leg and C leg; # denotes difference from preoperative values at P b 0.001.

3.3. Model of postoperative muscle atrophy The multiple regression model of percentage QF volume loss at four weeks post-ACL reconstruction revealed a significant (P = 0.008) relationship (r2 = 0.573) with the following equation: % QF volume loss = (− 0.090 ∗ preoperative QF volume deficit) + (2.707 ∗ preoperative QF MVICn) + (− 0.036 ∗ preoperative QF isometric endurance time) + (− 0.777 ∗ patellar girth) + (1.401 ∗ deficit of knee extension ROM) + 8.820. As shown in Table 1, the preoperative isometric endurance time Table 1 Independent variables included in multivariable linear regression model of percentage change in quadriceps femoris muscle volume at 4 and 12 weeks after anterior cruciate ligament reconstruction. β ± SE

b ± SE

P

Variables included at postoperative week 4 Intercept Preoperative QF volume deficit (%) Preoperative QF MVICn torque (Nm/kg) Preoperative QF isometric endurance time (s) Change in mid-patellar girth (cm) Deficit of knee extension ROM (%)

−0.127 0.376 −0.470 −0.135 0.578

± ± ± ± ±

0.193 0.235 0.176 0.193 0.177

8.820 −0.090 2.707 −0.036 −0.777 1.401

± ± ± ± ± ±

7.507 0.135 1.690 0.013 1.107 0.430

0.256 0.517 0.128 0.016 0.492 0.005

Variables included at postoperative week 12 Intercept Preoperative QF volume deficit (%) Preoperative QF MVICn torque (Nm/kg) Preoperative QF isometric endurance time (s) Change in mid-patellar girth (cm) Deficit of knee extension ROM (%)

−0.398 −0.080 −0.176 0.334 −0.213

± ± ± ± ±

0.229 0.278 0.231 0.225 0.227

16.726 −0.377 −0.722 −0.008 3.149 −0.637

± ± ± ± ± ±

9.278 0.217 2.513 0.011 2.123 0.680

0.088 0.100 0.777 0.457 0.155 0.361

MVICn, maximal torque of voluntary isometric contraction normalized to body weight; QF, quadriceps femoris muscle; ROM, range of motion; SE, standard error.


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had significant (P = 0.016) negative weight, indicating that subjects with better QF endurance lost less muscle volume than those with less QF endurance. In addition, the knee extension ROM deficit had significant (P = 0.005) positive weight, indicating that patients who had more knee extension deficit in this early postoperative period lost more muscle mass. In contrast, the multiple regression model for percentage change of QF volume at postoperative week 12 did not reveal a significant (P = 0.215) correlation (r2 = 0.306) (Table 1). 3.4. Correlates of muscle weakness There was a significant (P b 0.05) correlation (r2 = 0.457) between the percentage loss in QF MVIC torque and QF volume change at postoperative week 12 with the following equation: % QF MVIC torque loss = (1.520 ∗ change in QF volume) + 2.922. In addition, there was no significant difference in QF MVIC torque to volume ratio for either the leg (P = 0.515) or the time (P = 0.186) factor, but their interaction was significant (P = 0.047). Mean preoperative QF MVIC torque to volume ratios of the OP leg and the C leg were 0.123 ± 0.024 Nm/cm3 and 0.121 ± 0.025 Nm/cm3, respectively. The QF MVIC torque to volume ratios of the OP leg and the C leg at postoperative week 12 were 0.116 ± 0.022 Nm/cm3 and 0.123 ± 0.022 Nm/cm3, respectively (Figure 3(b)). The post hoc pairwise comparison revealed no significant differences in means of the QF MVIC torque to volume ratios. A large individual variation in percentage change of the QF MVIC torque to volume ratio was noted for both legs, postoperatively, ranging from −43.4% (decrease) to 40.0% (increase). 4. Discussion A moderate loss of QF volume was observed during the first 12 weeks after ACL reconstruction, with the lowest value at four weeks. Multivariable regression models partly confirmed our first hypothesis. Preoperative muscle capacity and postoperative joint recovery were predictive of QF atrophy at postoperative week 4. Our findings did not confirm our second hypothesis that muscle atrophy could explain the majority of postoperative QF weakness. Univariate regression demonstrated that 46% of the decrement in QF strength is explained by muscle atrophy, whereas the remaining portion can be attributed to changes in volitional activation of the prevailing muscle mass. As evaluated by QF MVIC torque to volume ratios, postoperative changes in volitional muscle activation were not uniform across patients, suggesting that factors not measured in the present study strongly influenced QF strength. 4.1. Changes in QF volume and strength The 5.8% preoperative deficit in muscle volume observed in our subjects was very similar to a 5.1% deficit previously reported for a mixed population of ACL deficient subjects [20]. Deficits in muscle volume of N9% can be expected only in a subpopulation of ‘non-copers’ [23]. Similarly, the 18% and 12% muscle loss observed at postoperative weeks 4 and 12, respectively, is consistent with previous observations at similar time points after ACL reconstruction with either STG [11] or patellar tendon [12] autograft. The muscle volume deficit of 17.4% observed in our subjects within the first 12 weeks post-surgery is similar to the 15% atrophy reported at seven months after ACL reconstruction [25], which suggests that a great majority of the QF loss develops in the early postoperative period. In contrast, the 20% QF strength deficit observed in the OP leg was lower compared to the 25% [19], 28% [10] or 31% [30] deficits previously reported at similar time points after surgery. Interestingly, QF strength deficits of up to 30% were recently reported at postoperative month 7 [25]. Taken together, the extent of postoperative QF atrophy and weakness observed in our sample was at the lower end of the previously reported values for the ACL-injured patient population. This may be attributed to the intensive rehabilitation programme used (see Section 2.2) and minimal or absent anterior knee pain during QF activation observed in our patients. The latter is consistent with previous reports of lower anterior knee pain after reconstruction with STG graft compared to patellar tendon graft [31]. Although low, the observed postoperative decreases in QF mass and strength were nevertheless a limitation for regaining normal knee function in our patient cohort. Exercise preconditioning programmes can be useful in this regard, provided that they are intensive enough and address key factors of QF atrophy and weakness of a given individual. Kim et al. [10] recently reported that patients preconditioned with a four week resistance training exercise programme (that focused mainly on improving QF strength) had ~ 5% lower deficits in isokinetic strength and single-leg hop performance at 12 weeks after ACL reconstruction than their counterparts not performing any type of preconditioning. Progressive resistance training exercise of ~75% 1 repetition maximum (RM) has been reported to have optimal effects in terms of preserving muscle strength in this population [9], suggesting that the rule of specificity holds true for the protective effect of preconditioning exercise. Another example of such specificity has been demonstrated by Hartigan et al. [9], who showed that the addition of perturbation balance exercises to a resistance preconditioning programme has no additional effect on preservation of QF isometric strength within six months after ACL reconstruction, but it increases excursion of the affected knee during mid-stance by reducing co-contractions of knee muscles and hence improving gait symmetry. However, not all preoperative resistance training exercise programmes have been shown to have a protective effect on postoperative QF mass and strength. As demonstrated by Shaarani et al. [12], a six week programme comprising resistance, endurance and balance exercises, prevented a decrease in knee function and modified Cincinnati score during the first 12 postoperative weeks, but at the same time failed to attenuate loss of QF mass, isokinetic strength and hopping performance. The lack of a protective effect in that study might be attributed to lower intensity of exercise (12 RM) and a less supervised training protocol,

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where two out of four weekly sessions were home-based and performed with resistive elastic bands [12]. This may have provided a lower level of intensity and reduced motivation than a supervised routine with free weights or resistive machines. It must be emphasized that the study by Shaarani et al. [12] is the only study where MRI measurements of QF size were performed both after training preconditioning and subsequent ACL reconstruction, thus no final conclusion can be drawn. More high-quality data is needed. 4.2. Factors associated with QF atrophy and weakness The results of multiple regression analyses revealed several important novel findings. Firstly, low isometric endurance was shown to be a significant predictor of QF atrophy during the first four weeks post-surgery (Table 1). QF contraction of low to moderate intensity has been consistently shown, by both EMG spectral properties [32] and single fibre CP content measurements [33], to recruit predominantly slow-twitch Type I motor units. The negative correlation between muscle endurance and postoperative loss of volume may thus provide indirect evidence of selective Type II fibre atrophy of the QF, which has been previously reported in ACL-injured or -reconstructed patients [22,34,35]. This view was also supported by the observed tendency, albeit nonsignificant (P = 0.128), for a positive correlation between preoperative MVICn torque and postoperative QF atrophy; which may imply that subjects with a higher percentage of Type II fibres lost their muscle mass to a greater extent. Preoperative QF volume deficit had a low and non-significant β-coefficient with postoperative muscle atrophy. This suggests that strong association between preoperative QF endurance capacity and its postoperative atrophy was not simply due to the fact that patients with more enduring QF were those initially more atrophied and thus remained more atrophied also after surgery. Secondly, the coupling of QF volume and joint knee extension recovery was mirrored by a significant correlation between postoperative passive deficit and loss of muscle volume during the first four postoperative weeks. This corroborates previous observations of close interdependence between QF activation and knee extension range in the first three months after ACL reconstruction [36]. Thirdly, QF atrophy was also strongly correlated with the deficit in knee extension ROM, which corroborates the inhibitory effect of reduced proprioceptive drive from the joint on QF volitional activation. A simple biomechanical explanation may be even more plausible; reduced knee extension compromises passive stability of the joint during weight transition to the limb, which prevents the patient from being able to fully load the OP leg. The non-significant β-coefficient between change in mid-patellar circumference and postoperative QF atrophy observed in our patients is in contrast to previous findings of AMI driven by intra-articular effusion. Namely, Palmieri-Smith et al. [13] demonstrated that 60 ml of saline injected into healthy knee joints is enough to reduce QF strength by 13%. Although the exact volume of effusion cannot be evaluated in our subjects, the mean increase in mid-patellar circumference of 1.2 ± 1.0 cm at postoperative week 4 may reflect a comparable joint effusion. We speculate that more specific and precise measurement of joint volume would enhance the strength of the observed relationship. 4.3. Changes in voluntary QF activation The level of voluntary muscle activation determined by the ratio between QF MVIC torque and its volume was almost identical in both legs prior to surgery; with absolute values being roughly 10% higher than those previously reported by Konishi et al. in either ACL-reconstructed [22] or healthy subjects [21]. Higher values are most likely due to use of maximal isometric rather than the isokinetic testing performed in our study. The comparison of relative ratio changes with time, which abolishes differences in strength measurement, revealed a significantly different change in the ratio on the OP leg postoperatively. However, the observed mean change was rather small, with a large standard deviation, which resulted in no different pairwise comparison. This may be explained by large individual differences in the QF activation ratio of the involved, but also of the uninvolved leg postoperatively; which is consistent with the findings of others (for a review see [37]). This observation does not seem to corroborate the paradigm of AMI being the primary mechanism of long-term deficits in QF strength after ACL reconstruction [17, 20–22], at least not in all individuals. In general, our observations corroborate the findings of Krishnan and Williams [3] and Thomas et al. [25] that muscle atrophy develops in all ACL-reconstructed patients, thus being the only factor clearly and significantly contributing to QF strength deterioration. The unexplained portion of change in muscle strength was over 50% and was predominantly explained by postoperative changes in volitional QF activation. However, these changes were not uniform in our patients and spanned from profound inhibition to substantial augmentation of QF activation. It thus appears that AMI was strongly expressed in some patients and was completely omitted in others. Although we did not systematically measure pain intensity using a visual analogue scale, the patients were repeatedly asked to report any discomfort or pain aggravation during test performance. Given that no pain was reported by our cohort, we assume that pain was not the key confounding factor affecting volitional QF activation and torque production. It must also be noted that other factors associated with disuse atrophy, that have not been studied here, such as (1) decrease in maximal torque capacity due to change in fibre type composition, (2) pennation angle and (3) moment arm, may have also contributed to the observed QF weakness. Although the contribution of these factors to the unexplained portion of strength decrement is probably less than that of volitional muscle activation, they may nevertheless play a significant role. 4.4. Limitations This study has some limitations. A small sample size reduces the strength of the multiple correlation models constructed from the five independent variables. In light of this limitation, a low threshold of co-linearity was set for variables that were entered


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into the model. It also needs to be emphasized that QF atrophy and strength loss were less than previously reported in ACLreconstructed patients, especially those with patellar tendon autograft. Patients with a preoperative QF strength deficit of ≥20% are likely to demonstrate a different pattern of postoperative QF deconditioning [6]. Therefore, our results cannot be extrapolated directly to patient populations reconstructed with other surgical techniques. Importantly, the indirect measure of QF activation used in our study must be compared with caution to results based on superimposed burst or interpolated twitch techniques. The latter measures derive changes in central activation ratio from the assumption that the sum of volitional muscle activation and supramaximal electrical stimulation represents true maximal contraction capacity of the muscle, whereas calculation of muscle volume to torque ratio simply attributes all changes in torque production, which are not explained by muscle mass, to changes in volitional activation. More specific indices of postoperative knee joint recovery, such as joint effusion volume, anterior knee laxity, pain patterns and intensity, as well as a rate of gain in extension ROM need to be used in future models of QF atrophy and weakness after ACL reconstruction. Understanding the relative roles of these factors would allow for more effective individualization of both preoperative and postoperative physiotherapy programmes. 5. Conclusions QF muscle atrophy in the first postoperative month after ACL reconstruction with STG autograft could be predicted using the studied variables, with isometric endurance and knee extension ROM deficit being the most significant contributors. An important novel observation was a strong inverse relationship between preoperative QF endurance and postoperative atrophy. In the studied cohort of patients, muscle atrophy explained 46% of QF weakness, whereas the remaining portion has not been satisfactory explained. The observed changes in volitional torque production for a given QF volume were less consistent in our patients than previously reported during a similar postoperative time period. Conflict of interest The authors declare that there are no conflicts of interest. 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