Crossover fatigue after unilateral submaximal eccentric contractions of the knee flexors involves peripheral alterations and perceived fatigue

doi:10.21203/rs.3.rs-1978469/v1

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Crossover fatigue after unilateral submaximal eccentric contractions of the knee flexors involves peripheral alterations and perceived fatigue

https://doi.org/10.21203/rs.3.rs-1978469/v1

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After a unilateral muscle exercise, the performance of the non-exercised contralateral limb muscle can be also impaired. This crossover fatigue phenomenon is still debated in the literature and very few studies have investigated the influence of eccentric contractions. This study was designed to assess neuromuscular adaptations involved in the crossover fatigue of the non-exercised contralateral hamstrings. Seventeen healthy young men performed a unilateral submaximal eccentric exercise of the knee flexors until a 20% reduction in maximal voluntary isometric contraction (MVIC) torque was attained in the exercised limb (EL). Before, immediately after exercise cessation (POST) and 24 hours later, neuromuscular function, global perceived fatigue and perceived muscle soreness were measured in both the EL and non-exercised limb (NEL). At POST, significant reductions in MVIC were observed in the EL (-28.1%, p < 0.001) and in the NEL (-8.5, p < 0.05). Voluntary activation decreased (-6.0, p < 0.05) in the EL only, while potentiated doublet torque were impaired (Dt100Hz -11.6%, p < 0.001 and Dt10Hz -8.1%, p < 0.05) in both the EL and the NEL. Global perceived fatigue significantly increased at POST (p < 0.001). Interestingly, peripheral alterations and global perceived fatigue may account for the crossover fatigue observed immediately after the exercise in the NEL possibly involving systemic adaptations.

contralateral

performance fatigability

voluntary activation

perceived muscle soreness

electromyography

After a strenuous unilateral exercise, a decline in muscle force or power production of the exercised muscle and/or an increase in subjective sensations (e.g., perceived fatigue, perceived muscle soreness) associated with the task performed is commonly reported. This reduced muscle force production defined as performance fatigability¹ is commonly attributed to interactions between peripheral and central factors including impairments of contractile function distal to the neuromuscular junction and adjustments within the central nervous system at the spinal and/or the supraspinal level ².Interestingly, during maximal or fatiguing unilateral contractions, involuntary increased electromyographic activity and force production are observed in the non-exercised contralateral homologous muscle^3,4. In addition, after a fatiguing unilateral exercise, performance fatigability can occur in the non-exercised contralateral muscle, but this observation is still disputed in the literature⁵.

Since the beginning of the millennium, numerous studies have sought to investigate the so-called “crossover” fatigue, defined here as the performance fatigability of a non-exercised contralateral homologous muscle following unilateral muscle exercise of the ipsilateral muscle ⁶. Although evidenced many times^4,7−11, some studies failed^12,13 to report crossover fatigue. A recent systematic review with meta-analysis⁵ concluded that the conflicting literature neither supports the existence of crossover fatigue nor “non-local muscle fatigue” (i.e., fatigue occurring in any non-exercised heterologous muscle). The moderators that were examined (i.e., study design, age, sex, training status, homologous vs. heterologous muscles, upper body vs. lower body, type of outcome measure, time of measurement, fatigue severity) had trivial effects on crossover fatigue. However, this meta-analysis did not take the influence of the type of contraction (i.e., dynamic or isometric) into consideration. While most of the crossover fatigue studies implemented isometric contractions^{4,7,10,11,14,15}, only four studies have used eccentric contractions, yet providing conflicting results^8,9,13,16.

Eccentric contractions are known to generate performance fatigability of the exercised muscles that can be associated with exercise-induced contractile alterations^17–19, delayed muscle soreness and pain^8,9, as well as central drive alterations^9,17−19. To date, after a unilateral eccentric exercise, increased ¹⁶, unchanged ¹³ or reduced force production ^8,9 is reported in the non-exercised contralateral homologous muscle. Due to the variability of the study designs, it is extremely challenging to explain the discrepancies observed among these studies. Interestingly enough, however, when considering the two studies that have evidenced crossover fatigue ^8,9, an interaction between central factors (i.e., reduced voluntary activation or muscle activity) and subjective sensations (i.e., increased perceived pain) seemed to contribute to the performance fatigability observed in the contralateral homologous muscle.

In crossover fatigue studies, the performance fatigability of the contralateral homologous muscle is generally assumed to encompass complex fatigue-induced central adjustments^20,21 possibly leading to reduced central drive to the non-exercised muscle^7,9−11. In addition, peripheral factors involving the dispersion of metabolites through the cardiovascular system and/or the presence of heat shock proteins in resting muscles have been assumed to account for the decreased performance of the non-exercised contralateral muscle^5,20 As far as we know, only one study reported an impairment of the resting electrically evoked twitch associated with reduced performance of the contralateral first dorsal interosseous muscle⁴. Finally, subjective sensations such as pain, effort or increased perception of fatigue could also contribute to the altered performance of the contralateral homologous muscle ^5,8,9,20, even though such measures were scarcely performed in crossover fatigue studies⁸. Consequently, even if the underlying mechanisms accounting for crossover fatigue are still debated, it has recently been proposed that a complex interaction between peripheral and central factors associated with increased subjective sensations is likely to occur⁵. This suggestion is in accordance with some of the results reported in the two crossover fatigue studies using unilateral eccentric exercise^8,9, although these two studies were not included in the meta-analysis.

To date, the occurrence of crossover fatigue in the knee flexors is still unknown. In this context, this study originally investigated the effect of unilateral submaximal eccentric exercise of the knee flexors on the crossover fatigue of the non-exercised contralateral homologous muscle. Concomitant assessment of neuromuscular function with measures of perceived fatigue and muscle soreness was intended to ascertain the influence of both peripheral and central factors and subjective sensations in crossover fatigue. Based on recent studies^8,9, we hypothesized that the submaximal eccentric fatiguing exercise would induce crossover fatigue, thus involving a cumulative central activation failure, peripheral alterations in both the exercised and non-exercised muscles and increases in perceived fatigue and muscle soreness. We also scrutinized the possible influence of involuntary increased electromyographic activity of the contralateral non-exercised muscles during the exercise of the ipsilateral muscle on crossover fatigue. Finally, due to the well-acknowledged long-lasting effect of eccentric exercises on performance fatigability^8,9, the performance of both the exercised and contralateral non exercised muscles were assessed 24 hours after the exercise.

Participants

Based on a recent study reporting cross-over fatigue after eccentric exercise⁹, G*Power (version 3.1.9.4; Kiel University, Kiel, Germany) was used to estimate sample size a priori. The sample size determination led to the participation of ten individuals in a repeated-measure, within-between interaction analyses with a power set at 0.95. Seventeen healthy young men [mean ± standard deviation (SD); age: 23.8 ± 4.6; body mass: 77.2 ± 10.2 kg; height: 180.5± 3.9 cm] took part in this study. A sensitivity power analysis (α = 0.05, power = 0.95) led to a large effect of f = 0.47 for the sample size of the participants included in this study. In order to be part of the study, participants had to be involved in regular recreational sport activities, free of any medical contraindication to physical activity. Neither could they have experienced musculoskeletal, neurological, or orthopedic disorder in the lower limbs for at least six months. All volunteers were fully informed about all risks, discomforts, and benefits of the study.

Measurements

Knee flexors’ torque

A specific ergometer (Hamtech device, Human Kinematic, Carros, France) allowing reliable and reproducible measurements in isometric and dynamic conditions²² was used to assess the unilateral force production of knee flexors of both lower limbs. A force transducer (S-beam, LS02-s, Tech Co. Ltd, Shenzhen, China; capacity: 1000N) was positioned 5 cm above the external malleolus on the Achilles tendon. A Biopac MP 150 (Biopac Systems, Inc., Goleta, CA., USA) was used to record force production at a sampling frequency of 1 kHz. Force was converted into torque during offline data processing using participants’ lever arms (i.e., distance between the lateral tibial condyle and the force transducer). The ergometer also included a potentiometer (P4500, Novotechnik U.S., Inc., Southborough, MA, USA) allowing measurements of angular velocity. To stabilize the participants’ pelvis during force production, two elastic bands were positioned ~5cm above participants’ sacroiliac joint and below the gluteal fold. Isometric contractions were measured on both the exercised (EL) and non-exercised (NEL) lower limbs in a standardized position with the hip and the knee flexion angles set at 40° and 30°, respectively (0° = full extension). Dynamic eccentric contractions of the EL started from a position combining 65° of hip flexion and 90° of knee flexion to a final position combining 40° of hip flexion and 30° of knee flexion.

Knee flexors’ surface electromyography

Surface electromyography of the biceps femoris (BF) muscles of both lower limbs was collected using pairs of surface electrodes (Ag-AgCl, diameter = 10mm; inter-electrode distance = 20mm; Contrôle-Graphique, Brie-Comte-Robert, France) placed in accordance with the SENIAM recommendations²³. A reference electrode was placed on the lateral tibial condyle of the tested lower limb. Indelible ink marks ensured identical repositioning during the entire experiment. Low-resistance impedance (< 3kΩ) was obtained by shaving and slightly abrading the skin with emery paper. Electromyographic signals were recorded at a sampling frequency of 2 kHz using the Biopac MP150 system (Biopac Systems, Inc., Goleta, CA, USA; bandwidth frequency = 10 – 500Hz, common mode rejection ratio = 110dB, Z Input = 1000MΩ, gain = 1000).

Knee flexors’ electrical stimulation

Percutaneous electrical myostimulation (400V and 1ms duration rectangular pulse) was delivered by an electrical stimulator (DS7, Digitimer Ltd., Hertfordshire, UK) through self-adhesive rectangular electrodes (5cm × 9cm - Stimex, Wetzlar, Germany) placed on the participants’ lower limbs. The cathode was positioned on the hamstrings’ proximal part (i.e., below the gluteal fold) and the anode was located at the popliteal fossa. Electrodes positions were marked on the skin to guarantee similar placement during the entire experimental procedure. Maximal twitch force and maximal amplitude of the BF compound muscle action potential were determined at rest by progressive stimulation intensity increments on both lower limbs. The stimulation intensity was further increased by 20% (EL: 142.1 ± 24.9mA, NEL: 148.2 ± 31.0) to warrant adequate assessment of knee flexors’ neuromuscular function.

Ratings of perceived fatigue and muscle soreness

The notion of perceived fatigue, which was explained to the participants as “a feeling of diminishing capacity to cope with physical stressors”²⁴ was assessed using the French translated and validated version of the Rating-of-Fatigue Scale ²⁵. Ratings of perceived fatigue (RPF) accounting for participants’ general fatigue were scored from 0 to10 (0, not fatigued at all; 10, total fatigue and exhaustion – nothing left).

Perceived muscle soreness (PMS) was recorded in both lower limbs using a visual analog scale. A steady 25-N pressure was applied with a 0.5cm diameter cylindrical object just above and below surface electromyography electrodes of the BF on both the EL and NEL²⁶. Participants had to score their pain perception from 0 to10 (0, no pain; 10, worst pain).

Experimental procedure

The participants were required to attend the laboratory in three occasions (Fig. 1): i) a familiarization session, ii) a testing session including the different measurements realized before (PRE) and immediately after (POST) the unilateral fatiguing exercise (Session 1), and iii) a testing session performed 24 hours after the fatiguing exercise (POST24; Session 2).

One week prior to the testing session, participants were acquainted with the equipment, the experimental procedures, and the neuromuscular function assessment (see details below) on both limbs. During the familiarization session, a particular focus was put on the angular velocity to be maintained (i.e., 10°.s^-1 provided by real time feedback on a screen placed in front of the participants) during the unilateral eccentric contractions of the EL. Once fully familiarized with all the procedures on both limbs, the 1 Repetition Maximum eccentric contraction (1RM ECC) of the EL was determined by adding loads until the participant could no longer control the angular velocity of 10°.s^-1.

The two testing sessions (i.e., Session 1 - PRE and Session 2 - POST24) started with the measures of RPF and PMS scores. A standardized warm-up including the “Extender” and the “Diver” exercises ²⁷ and a single-leg bridges exercise were performed on both limbs for each exercise (i.e., 2 sets of 6 repetitions), followed by 10 submaximal isometric contractions of both limbs in the isometric testing position. The intensity of the submaximal contractions (i.e., in the percentage of perceived maximal force production) was progressively increased (i.e., ~30%, 4 contractions; ~50%, 3 contractions; ~70%, 2 contractions and ~90%, 1 contraction). Then, neuromuscular function was assessed as follows: i) two maximal voluntary isometric contractions (MVIC) with a 100-Hz superimposed paired electrical stimulation delivered over the MVIC plateau, followed by potentiated stimulations elicited at rest at 2 (100Hz paired stimulus), 4 (10Hz paired stimulus) and 6 s (1Hz single stimulus), and ii) the determination of the 1RM ECC of the EL. The EL was always tested first followed by the NEL measures. For the measurements performed immediately after the unilateral fatiguing exercise (i.e., POST), only one MVIC with superimposed and potentiated stimulations was assessed on both the EL and NEL, followed by the measure of RPF and PMS scores.

Unilateral fatiguing eccentric exercise

The fatiguing exercise involved repetitive sets of five unilateral eccentric contractions of the EL knee flexors at 80% of the 1RM ECC measured in PRE. Contractions were performed at an angular velocity of 10°.s^-1 (i.e., contraction duration: ~5s). After each contraction, participants were passively lifted into the starting position by experimenters, providing a 10-s rest period. A 25-s rest interspaced sets of submaximal eccentric contractions. A MVIC of the EL was performed at the end of each set to evaluate the level of force decrement. Sets were repeated until a 20% MVIC force decrement was reached on EL.

Data analysis

For PRE, POST and POST24 measurements, the highest MVIC peak torque value produced by both lower limbs was retained for data analysis. Root mean square (RMS) values of BF surface electromyography signals were calculated during a 500-ms period over MVIC. BF RMS was normalized to the respective BF compound muscle action potential (i.e., BF RMS/M) recorded at each time point. Potentiated torques evoked by electrical paired stimuli at 100 Hz (Dt_100Hz) and 10 Hz (Dt_10Hz) were used as peripheral fatigue indicators. The ratio Dt_100Hz-to-Dt_10Hz (Dt_10Hz/Dt_100Hz) was also computed. Along with BF RMS/M, the maximal voluntary activation level (VA) and the central activation ratio (CAR) of the knee flexors were calculated and served as central fatigue indicators ^28,29. VA and CAR were computed according to the following formula:

During the unilateral fatiguing eccentric exercise, the number of contractions performed and the amount of total work calculated using torque-time integral (i.e., area under the torque-time curve) were collected. The amount of work produced was summed in four consecutive periods that represented 25% of the total duration of the exercise. The MVICs measured at the end of each set and expressed as a percentage of the initial MVIC value produced at PRE were linearly interpolated between the nearest values at 25%, 50% and 75% of the number of sets in order to describe the evolution of the participants’ MVIC throughout the entire duration of the fatiguing exercise. Similarly, the BF RMS of both the EL and NEL (computed over the entire 5s duration of the contraction) and expressed as a percentage of the initial value measured at PRE were linearly interpolated between the nearest values at 25%, 50% and 75% of the exercise. The MVIC and BF RMS values retained at 100% of the number of sets performed corresponded to the value measured after the last set of each participant.

Statistical analyses

The normality of the distribution of each variable was tested using the Kolmogorov–Smirnov test. For normally distributed data, a repeated measures two-way ANOVA (limb × time) was performed to assess fatigue-induced adaptations. For non-normal distribution, the data was processed through the nonparametric Aligned Rank Transform (ART) procedure³⁰ using ARTool (v. 2.1.2) for main, interaction and post hoc pairwise comparisons (ART-C procedure)³¹. Separate ANOVAs were performed on ART responses. The effect size of each ANOVA was estimated from partial eta square (η²p) values and considered as small when ~0.01, medium when ~0.06 and large when ≥ 0.14. Bonferroni post-hoc tests were used when a significant interaction or main effect was observed. The nonparametric Friedman test with Conover’s post hoc comparison with a Bonferroni correction was conducted on the RPF and PMS scores of both the EL and NEL. The effect size was calculated from the Kendall’s coefficient of concordance (Kendall’s W). During the unilateral fatiguing eccentric exercise, separate repeated-measures ANOVAs tested the time course of MVICs and total work and a repeated measures two-way ANOVA (limb × time) was performed to assess the time course of BF RMS values of both the EL and NEL. Significance was set at p < 0.05. Statistical analyses were performed using Statistica (Statsoft, version 8.0 Tulsa, OK, USA) or JAPS (v. 0.14) software. Unless specified, normally distributed data is expressed as mean ± SD (standard deviation) and non-normally distributed data is displayed as median (interquartile range) in the manuscript, in the tables and figures.

Unilateral eccentric fatiguing exercise

The number of contractions performed and the total work produced were 37.65 ± 14.59 and 54208.33 ± 21034.52 N.m.s^-1, respectively.

Throughout the fatiguing exercise, a significant reduction of both the MVIC (F_(4,64)= 43.58; p<0.001; η²p = 0.73) and the torque-time integral (F_(3,48) = 4.93; p<0.01; η²p = 0.24) was observed. At the end of the fatiguing exercise, the MVIC, expressed as a percentage of the initial value, was lower than the MVICs produced at PRE, 25, 50 and 75% of the fatiguing exercise duration (p<0.001; Fig. 2a). The amount of work achieved during the last quarter of the fatiguing exercise duration was smaller than the one produced during the first quarter (p<0.01; Fig. 2a). A significant main effect of the limb was noted for the BF RMS values during the fatiguing exercise (F_(1,32) = 71.86; p<0.001; η²p = 0.69; Fig. 2b) with pooled mean values of the EL (54.35 ± 21.67%) greater than those of the NEL (9.33 ± 4.74%).

PRE, POST and POST24 measurements

MVICs

A significant limb × time interaction was observed for MVIC (F_(2,64)= 9.12; p<0.001; η²p = 0.22). A significant reduction in MVIC was observed between PRE and POST in the EL (-28.09 ± 6.47%; p<0.001; Fig. 3a) and in the NEL (-8.52 ± 16.16%; p<0.05; Fig. 3a). MVIC torques measured at POST24 were no longer different from PRE values for both limbs (p>0.05).

Central and peripheral fatigue indicators

After ART-C procedure, a significant limb × time interaction was observed for both VA (F_(5,96) = 11.09; p<0.001; η²p = 0.37) and CAR values (F_(5,96) = 11.41; p<0.001; η²p = 0.37). A significant decrease in VA (-6.00 ± 8.24%; p<0.05; Fig. 3b) and CAR (-1.99 ± 2.48%; p<0.01; Table 1) was observed between PRE and POST in the EL, whereas no significant modification was noticed in the NEL. At POST24, VA and CAR had returned to PRE values. Following ART-C procedure, no significant change was found in the BF RMS/M values in both limbs (p>0.05; Table 1). After ART procedure, no modification of the BF compound muscle action potential values was observed (p>0.05; Table 1).

While no limb × time interaction was noted, a significant time effect was observed in both the Dt_100Hz(F_(2,64)= 8.74; p<0.001, η²p = 0.21; Fig. 3c) and the Dt_10Hz (F_(2,64) = 3.62; p<0.01, η²p = 0.10; Fig. 3d). Independently of the limb, Dt_100Hzand Dt_10Hz, decreased between PRE and POST (-11.56 ± 17.94%; p<0.001 and -8.07 ± 24.23%; p<0.05, respectively). POST24 values were not different from PRE values anymore (p>0.05). No interaction nor main effect was found for the Dt_100Hz-to-Dt_10Hz ratio (p>0.05).

Perceived fatigue and muscle soreness scores

RPF scores were significantly increased at POST compared to PRE (χ² (2) = 26.79; p<0.001; Kendall’s W: 0.42; Table 1). A significant increase of PMS scores (χ² (2) = 6.78; p=0.03; Kendall’s W: 0.68; Table 1) was noted in the EL with greater scores at POST24 compared to PRE (p<0.05) whereas no modification of the PMS scores in the NEL was observed (p>0.05).

Table 1. Median (interquartile range) of neuromuscular function and perceived muscle soreness (PMS) of both the EL (exercised limb) and the NEL (non-exercised limb) as well as global perceived fatigue (RPF). Bold values are significant. ^*, ^** and ^*** significantly different from PRE values at p<0.05, p<0.01 and p<0.001, respectively. BF Biceps Femoris, BF RMS/M Root Mean Square values of BF muscle normalized to the compound muscle action potential.

		PRE	POST	POST24
Voluntary Activation (%)	EL	99.75 (0.19)	97.87 (5.14)^*	99.74 (0.66)
	NEL	99.59 (0.44)	99.60 (0.14)	99.19 (0.61)
Central Activation Ratio (%)	EL	99.90 (0.05)	99.09 (1.66)^**	99.93 (0.31)
	NEL	99.88 (0.16)	99.89 (0.06)	99.76 (0.20)
BF RMS/M (a.u.)	EL	0.15 (0.16)	0.12 (0.13)	0.17 (0.08)
	NEL	0.07 (0.08)	0.08 (0.07)	0.08 (0.06)
BF compound muscle action potential (mV)	EL	3.04 (4.08)	2.33 (5.27)	3.00 (4.61)
BF compound muscle action potential (mV)	NEL	3.04 (2.53)	2.88 (1.78)	2.96 (2.80)
PMS (0-10)	EL	0.00 (0.75)	0.25 (1.50)	0.75 (1.50)^*
	NEL	0.00 (0.50)	0.00 (0.75)	0.25 (1.00)
RPF (0-10)		0.00 (2.00)	7.00 (1.00)^***	2.00 (2.00)

This is the first study that highlights the occurrence of crossover fatigue on the knee flexors. The main findings of this study were: i) MVICs of both the EL (-28%) and the contralateral NEL (-9%) were impaired immediately after the exercise, ii) MVIC reduction of both limbs appeared to be related to an overall impairment of contractile function and an increase in global perceived fatigue, iii) performance fatigability of the EL also involved voluntary activation failure, and iv) during the exercise of the ipsilateral EL, involuntary electromyographic activity of the contralateral NEL did not exceed 10% of its maximal electromyographic activity.

To date, no study has investigated the effects of a unilateral exercise on the performance fatigability of the knee flexors of the exercised limb and its influence on performance fatigability of the contralateral homologous muscles. The immediate 28% MVIC decrease of the EL observed in the current investigation after an eccentric exercise is in line with the previous studies performed on other muscle groups showing MVIC impairment ranging from 16 to 50%^8,9,13. Eccentric exercise is known to impair muscle contractile function, generally assessed through the measure of electrically evoked torques, immediately and/or during many days after the exercise^9,17,18. Accordingly, we observed an immediate (i.e., between PRE and POST) reduction of both Dt_100Hz (-12%) and Dt_10Hz (-8%) in the EL with no modification of the Dt_100Hz-to-Dt_10Hz ratio. Since the BF compound muscle action potential values were unaffected by the eccentric exercise (i.e., sarcolemma excitability unchanged), the reduction of electrically evoked torques was a possible consequence of excitation-contraction coupling failure including increased intramuscular metabolites concentrations leading to impaired calcium release and/or decreased calcium sensitivity^32,33. Structural damage to muscle fibers³⁴ often assessed through the measure of perceived muscle soreness could also contribute to MVIC decreases. Contrary to a previous study performed on the knee flexors³⁵, no modification of PMS scores was observed immediately after our unilateral eccentric exercise. This contradictory observation might be ascribable to the smaller amount of MVIC decrease observed here in comparison with Paschalis et al.’s³⁵ study (i.e., -28% vs -45%). Consequently, the knee flexors performance fatigability of EL is due to an impaired muscle contractile function involving excitation-contraction coupling failure.

In addition to peripheral alterations, the presence of immediate central alterations in the EL was underlined by significant decreases in knee flexors’ VA (-6%) and CAR (-2%). Although previous experiments^36,37 report non-significant changes ranging from 1.6 to 4.5% of the knee flexors’ voluntary activation after ecologically induced fatigue (i.e., simulated soccer match and repeated sprints), this is the first study that has underlined significant central alterations on this muscle group after a unilateral submaximal eccentric exercise. So far, only one study reported a 7% significant decrease of voluntary activation after a unilateral submaximal eccentric exercise but it was performed on the plantar flexor muscles⁹. In addition, these authors did not observe a central activation ratio values change. Because the measures of VA and CAR do not allow dissociating spinal from supraspinal changes, central alterations may have occurred at both levels^2,38. The possible rise in intramuscular metabolites concentration associated with fatiguing exercises is known to increase the inhibitory actions from groups III-IV afferents which are highly activated during eccentric contractions^39,40. Groups III and IV afferents can modulate the descending central drive at both spinal (i.e., H-reflex studies)^41–43 and supraspinal level (i.e., corticospinal excitability studies)^19,39,43 after eccentric exercises on other muscle groups. However, it is extremely challenging to ascertain the exact origin of this modulation due the conflicting results reported in these studies. Central alterations were also assessed through the changes in the electromyographic activity (i.e., RMS/M) of the BF muscle, but no change was observed. However, only BF muscle activity was measured, which does not represent the entire descending central drive sent to the hamstrings. Along with central alterations, another interesting and original result of the present study that can be noted is the significant augmented RPF scores noted immediately after the exercise. A recent study also reported similar observations on the knee extensors after a submaximal fatiguing eccentric exercise¹⁸.Then, we can put forward the hypothesis that our submaximal eccentric exercise of the knee flexors is likely to lead to a global feeling of fatigue. To summarize, we originally observed that a unilateral submaximal eccentric exercise led to impaired performance fatigability of the knee flexors of the EL (including peripheral and central alterations) associated with a concomitant increase in perceived fatigue, thus accounting for the possible interaction between these two attributes⁴⁴.

The 28% MVIC decrease observed on the EL led to a significant 9% MVIC drop in the contralateral NEL, evidencing crossover fatigue in the knee flexors for the first time. Our result agrees with MVIC impairments of -13.7% and -7% reported after a unilateral eccentric exercise in the contralateral knee extensors and plantar flexors, respectively^8,9. The involuntary increases of electromyographic activity and force production reported in the non-exercised contralateral homologous muscle during maximal or fatiguing unilateral contractions of the ipsilateral muscle^3,4 could partly contribute to crossover fatigue. Although observed in the first dorsal interosseous muscle, progressive increases of the electromyographic activity up to 38% of the maximal activity were reported with a crossover effect of ~10%⁴. Here though, the BF electromyographic activity of the NEL remained stable throughout the fatiguing exercise and corresponded to ~9% of its maximal electromyographic activity recorded during MVIC at PRE. Consequently, this level of activity is highly unlikely to have contributed to the MVIC reduction of the NEL.

Nevertheless, and to the same extent as in the EL, both Dt_100Hz (-12%) and Dt_10Hz (-8%) of the NEL were reduced immediately after the exercise. To the best of our knowledge, impaired electrically evoked torques in the contralateral homologous muscle after a unilateral exercise were only reported once in the literature after isometric exercises⁴. More recently, even if Marathamuthu et al.⁹, observed a crossover fatigue in the non-exercised muscle group after a submaximal eccentric exercise, the resting twitch did not change. Muscle groups studied (i.e., plantar flexors vs. knee flexors) and/or methodological (i.e., single resting twitch vs. double potentiated twitch) differences could account for this discrepancy with our investigation. A first explanation for the electrically evoked torques alterations of the present study could be related to the spreading of metabolites from the EL to the NEL via the cardiovascular system. Although speculative here, such observations were evidenced in lower limb muscles following an intense upper limb muscles exercise^45,46. Second, in an animal study, the expression of heat shock proteins increased immediately in the homologous contralateral muscle following a fatiguing exercise of the ipsilateral muscle induced by electrical stimulation⁴⁷. Thanks to their experimental design, these authors concluded that both the sympathetic system and the neural system (e.g., through group III and IV afferents activation) were responsible for the higher expression of heat shock proteins in the contralateral muscle but also in other remote resting muscles. Although future studies should clearly investigate these adaptations in human contralateral homologous muscles, it may be assumed that our submaximal eccentric exercise of the knee flexors led to a systemic adaptation involving cardiovascular and neural systems.

A recent study has also suggested that systemic adaptation could explain eccentric-induced crossover fatigue⁹. In this study, greater muscle soreness was reported immediately after the exercise and the authors argued that pain perception contributed to their significant 3.5% reduction of voluntary activation observed on the contralateral muscles. As opposed to that, in our study, the PMS scores, VA and CAR of the NEL remained unchanged. However, considering the significant increases in RPF scores, it cannot be ruled out that a general feeling of fatigue can contribute to a global systemic adaptation accounting for the crossover fatigue observed in our investigation. Taken together, the peripheral alterations also observed in the NEL associated with greater perceived fatigue reinforce the possible influence of a systemic adaptation after our submaximal eccentric exercise.

Recent eccentric-induced crossover fatigue studies have shown impairment of force in the contralateral muscles that can last up to 48 hours^8,9. We therefore assessed both EL and NEL 24 hours after the exercise (POST24), but performance fatigability of the knee flexors and perceived fatigue had been fully recovered. Then, our observations conflict with previous studies showing prolonged crossover fatigue. Although the muscle groups tested and the fatiguing exercise differed from the present investigation, both studies reported significant muscle pain up to 48 hours⁸ and even 72 hours⁹ in the contralateral limbs after their eccentric exercise, which could account for the performance fatigability of the non-exercised muscle. Here, performance fatigability of the knee flexors was not significantly impaired anymore at POST24, despite the likely presence of muscle damage indicated by the increase in PMS scores in the EL only. It might be suggested that this perceived muscle soreness at POST24 could still be involved in the non-significant -4.6% reduction of the MVIC of the EL. Future studies should ascertain the long lasting effects of eccentric exercise on crossover fatigue.

Unilateral submaximal eccentric hamstring exercise undeniably induced immediate crossover fatigue. The decrease in force production observed in both limbs has a different etiology. On the one hand, the central activation failure and peripheral alterations (i.e., performance fatigability) associated with global perceived fatigue (i.e., perceptions of fatigue) can account for the exercise-induced fatigue in the EL. On the other hand, the crossover fatigue in the NEL may be ascribable to a systemic adaptation involving peripheral alterations and global perceived fatigue. Originally, we observed impaired electrically evoked torques in the NEL, but the exact mechanism accounting for this result has still to be further investigated. Finally, a compensatory mechanism involving an involuntary increase of the electromyographic activity in the NEL did not contribute to the crossover fatigue.

Data availability

The datasets generated during the present study are available from the corresponding author on reasonable request.

Ethics declarations. Approval was obtained from the Ethics Committee (Protection Committee of People for Biomedical Research Southeast III, France; Authorization Number 2020-A02811-38), were conducted in accordance with the latest version of the Declaration of Helsinki (2013).

Acknowledgements

This work has been partly supported by French government, through the UCA^JEDIInvestments in the Future project managed by the National Research Agency (ANR) with the reference number ANR-15-IDEX-01.

Author contributions

J.G., F.M., F.D.S., B.C., E.P., J.B., and S.S.C. conceived and designed the experiments. J.G., F.M., F.D.S., B.C., and F.M. conducted the experiments. J.G., F.D.S., B.C., J.B., and S.S.C. analyzed data. J.G., and S.S.C. wrote the first draft of the manuscript. All authors contributed to the interpretation of the results, edited, critically revised and approved the final version of the manuscript.

Competing interests

The authors declare no potential conflict of interest.

Consent to participate.

All participants included in the study signed an informed consent form.

Consent for publication.

Participants signed informed consent regarding the anonymized publication of the data collected during this study.

Additional information

Correspondence and requests for materials should be addressed to S.S.C.

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No competing interests reported.

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Crossover fatigue after unilateral submaximal eccentric contractions of the knee flexors involves peripheral alterations and perceived fatigue

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