Markers of force-generating capacity.

MVC torque. As expected, we found that time-course of MVC torque recovery was different between clusters (Fig 4B). MVC torque recovery was faster in the LOW and MOD clusters when compared with the HIGH cluster (Fig 4B). Indeed, a large effect of exercise on MVC torque (SMD = -1.18 ± 0.12) was still observed at 72 h in the HIGH cluster whereas small to moderate effects were found for the other clusters (LOW: SMD = -0.14 ± 0.05; MOD: SMD = -0.50 ± 0.06).

Jump height. Jump height showed greater decrease at 24–48 h post-exercise in the HIGH (SMD = -2.13 ± 0.72) than in the LOW (SMD = -0.47 ± 0.14) cluster after exercise (Fig 4F). Moreover, recovery was faster in LOW and MOD clusters when compared with the HIGH cluster. A large effect of exercise on jump height (SMD = -1.95 ± 0.28) was still observed at 72 h post-exercise in the HIGH cluster, whereas small effects were found for the other clusters (LOW: SMD = -0.44 ± 0.14; MOD: SMD = -0.21 ± 0.29).

Evoked torque response. A significant decrease in the amplitude of the evoked torque response was observed during the days following the exercises (Fig 4C). The decrease at 24–48 h post-exercise was larger for HIGH cluster (SMD = -1.21 ± 0.23) compared to the LOW (-0.33 ± 0.16) cluster (Fig 4D). The recovery took longer (> 96 h) in the HIGH cluster than MOD and LOW clusters (48 h) (Fig 4D). Indeed, a large effect of exercise on the amplitude of the evoked torque response was still observed at 48, 72 and 96 h post-exercise, whereas small to moderate and no effects were evident for the MOD and LOW clusters, respectively (Fig 4D).

Voluntary activation level. VAL was significantly decreased at <6 h (SMD = -0.71 ± 0.20) and 48 h (SMD = -0.36 ± 0.11) after the exercise (Fig 3). Time-course of this marker was not analyzed for each cluster due to lack of experimental groups in at least one cluster.

Rate of torque development. A moderate to large decrease of RTD was observed after the exercise (Fig 3). RTD reduction was the largest within 6 hours following exercise (SMD = -1.18 ± 0.24), transiently recovered at 24 h post-exercise (SMD = 0.53 ± 0.28; p = 0.06) and decreased again at 48 h post-exercise (SMD = -1.01 ± 0.26). Time-course of this marker was not analyzed for each cluster due to lack of experimental groups in at least one cluster.

Range of motion.

A significant decrease in ROM was observed during the days following the exercises (Fig 4G). However, ROM was significantly reduced only in the MOD and HIGH clusters and the maximum decrease occurred at 48 h post-exercise for these clusters (SMD: -1.14 ± 0.48 and -1.29 ± 0.39, respectively) (Fig 4H). Moreover, ROM was reduced earlier after the end of the exercise in HIGH cluster (<6 h) compare to MOD cluster (48 h).

Delayed-onset muscle soreness.

Increase in active and passive DOMS and decrease in PPT were observed and peaked 24 to 48 h after exercise (Fig 5A and 5C). DOMS peaked at 48 h post-exercise in the HIGH cluster but peaked at 24 h post-exercise in the LOW and MOD clusters. Moreover, the recovery was faster for the LOW compared to the MOD and HIGH clusters (Fig 5B and 5D). A large effect of exercise on active/passive DOMS was still observed at 72–96 h post-exercise in the HIGH cluster, whereas small to moderate effects were seen for the other clusters at these time points (Fig 5B and 5D).

Swelling.

Limb circumference. A small decrease in limb circumference was observed only at 24 h post-exercise (SMD = 0.35 ± 0.15; Fig 3). Time-course of this marker was not analyzed for each cluster due to lack of experimental groups in at least one cluster.

Transverse relaxation time. T₂ was significantly increased after exercise (Fig 3). Although no study assessed T₂ at <6 h post-exercise, larger increases in T₂ were observed at 48 to 96 h post-exercise (Fig 3). Time-course of this marker was not analyzed for each cluster due to lack of experimental groups in at least one cluster.

Blood markers.

Creatine kinase (CK) activity. CK activity peaked, on average, 24 h post-exercise and remained elevated for up to 96 h post-exercise (Fig 5E). The time-course changes in CK activity differed as a function of clusters (Fig 5F). CK activity peaked 24 h after exercise for the LOW (SMD = 1.08 ± 0.14) and MOD (SMD = 0.92 ± 0.08) clusters and 72 h post-exercise for the HIGH cluster (SMD = 1.94 ± 0.27) (Fig 5F).

Myoglobin (Mb) concentration. Mb concentration peaked, on average, within 6 h and remained elevated for up to 96 h post-exercise (Fig 5G). The time-course of changes in Mb concentration also differed as a function of clusters (Fig 5H). The recovery of Mb concentration was longer in the MOD and HIGH clusters (< 96 h) when compared with the LOW cluster (24 h) (Fig 5H). The maximal Mb concentration was larger for the HIGH cluster (SMD = 2.58 ± 0.60) than the LOW (SMD = 0.66 ± 0.32) cluster.

Lactate dehydrogenase (LDH). LDH activity peaked 48 h post-exercise (SMD = 1.28 ± 0.24; Fig 3) remained elevated for up to 96 h post-exercise (SMD = 0.95 ± 0.31; Fig 3). Time-course of this marker was not analyzed for each cluster due to lack of experimental groups in at least one cluster.

Interleukin-6 (IL-6). Moderate increase in IL-6 concentration was observed <6 h after exercise (SMD = 0.51 ± 0.15; Fig 3). IL-6 was significantly increased only during the first 2 days following exercise (<6 h, 24 h and 48 h; Fig 3). Time-course of this marker was not analyzed for each cluster due to lack of experimental groups in at least one cluster.

Associations within 6 h post-exercise.

Changes in MVC torque within 6 h post-exercise was significantly correlated (r² = 0.67; p < 0.001) with changes in MVC_{loss 24-48h}. Jump height, ROM, active DOMS, limb circumference, VAL and Mb concentration changes observed within 6 hours after exercise (SMD value at <6 h) were also correlated with the largest changes in MVC_{loss 24-48h} (Table 2).

Associations between 24 and 48 h post-exercise.

Jump height, PPT, limb circumference, amplitude of the evoked torque response, RTD and T₂ changes observed at 24 h post-exercise were correlated with the largest change in MVC_{loss 24-48h} (Table 2). Similarly, ROM, active/passive DOMS, limb circumference, amplitude of the evoked torque response and T₂ changes observed at 48 h post-exercise were correlated with the largest change in MVC_{loss 24-48h} (Table 2).

Associations later than 48 h post-exercise.

Jump height performance, active/passive DOMS, PPT, limb circumference, evoked torque response, VAL and CK activity changes observed at 72 h post-exercise were correlated with the largest change in MVC_{loss 24-48h} (Table 2). Similarly, active DOMS, evoked torque response and RTD measured at >96 h post-exercise were correlated with MVC_{loss 24-48h} (Table 2).

Markers of force-generating capacity.

The results of the present study showed that the larger the MVC_{loss 24-48h} of the lower limb muscles, the longer the recovery (Fig 4B). This is consistent with Damas et al. [13] that reported time-course differences between three clusters computed from individual MVC torque loss after maximal eccentric exercise of the elbow flexors. The MVC torque recovery time-course is also consistent with a previous review by Paulsen et al. [11] who showed a longer recovery after “severe damage” compared to “mild” or “moderate” EIMD based on the MVC torque loss. Interestingly, we also found that the larger the MVC_{loss 24-48h} (i.e., the larger EIMD), the longer the evoked torque response and jump height recovery. Unfortunately, we were unable to compare time-course of VAL and RTD at different levels of MVC_{loss 24-48h} due to lack of studies assessing these markers in at least one cluster. However, we found that VAL was decreased during the first hours after the exercise (<6 h) and at 48 h post-exercise. RTD, a measure of ability of the neuromuscular system to rapidly produce torque during MVC, was decreased in the first hours following exercises (<6 h), but also 48 to 96 h post-exercise. As the ability of neural drive to activate muscle (i.e., VAL) was not affected 72 and 96 h after exercise in the present study, it could be speculated that the decreased RTD at these time points was likely due to peripheral factors. Consistently, it has been suggested [24, 25] that early phase RTD reflects neural mechanisms underlying exercise-induced torque loss, while late RTD may describe the same physiological mechanisms as MVC torque loss. The results of evoked torque response and VAL confirmed that MVC torque loss observed the hours/days after an EIMD event are due to peripheral (i.e., muscular) and central (i.e., nervous) alterations of the neuromuscular system. Moreover, we confirmed that recovery process to reestablish the force-generating capacity after a training session or an exercise intervention must be individually adapted as a function of extent of MVC_{loss 24-48h}.

DOMS, ROM, and swelling.

The present review confirmed that both passive and active DOMS peaked between 24 and 48 h after exercise, and showed that the greater the MVC_{loss 24-48h}, the later the peak of DOMS occurs. Indeed, we found that DOMS peaked at 24 h after the exercise for LOW and MOD clusters, whereas it peaked at 48 h post-exercise for HIGH cluster. These results were not consistent with those reported by Damas et al. [13] who found that DOMS peaked 48 h after eccentric exercise of the elbow flexors, regardless of the level of MVC torque loss. Theses discrepancies could be due to the large type of exercise modalities, muscle groups and study designs included into the analysis in the present review, which differ from the specific model used by Damas et al. [13]. However, it is difficult to fully explain the delayed peak of DOMS after severe EIMD due to a complex etiology of pain [26]. For instance, muscle inflammation due to white cells infiltration (i.e., macrophages) [11] and intramuscular fluid pressure [27] due to muscle swelling could be different as function of the level of MVC_{loss 24-48h}, inducing different time-courses of DOMS. Our results showed a small increase of limb circumference at 24 h post-exercise, whereas larger T₂ MRI imagining elevation was observed 24 to 96 h post-exercise. As Damas et al. [13] reported that eccentric exercise of the elbow flexors induce an increase in limb circumference up to 120 h regardless of the level of MVC_{loss 24-48h}, it could be speculated that this marker is more sensitive in upper limbs than lower limbs. Our results showed that ROM was not reduced the days after the exercises for the LOW cluster, while ROM decreased greatly at 48 h post-exercise for the MOD and HIGH clusters. Moreover, ROM was decreased within few hours (<6 h, 24 h) following exercise only in the HIGH cluster. In a clinical or sport context, reproducible, cheap, quickly and easy to use evaluations are important in order to provide a rapid and quantitative diagnosis of the impact of the exercise on the whole muscle system functionality. It could be suggested the assessment of limb circumference could be most appropriate and give more information about muscle swelling or EIMD when the damage is induced on the upper limbs muscles [9, 13]. Moreover, it seems that changes in muscle-tendon stiffness and the presence of edema represented by the measure of ROM [28] could be appear earlier (within the hours after exercise) and stay high longer (72 h) after severe EIMD.

Blood markers.

Contrary to the above-mentioned indirect markers, circulating blood markers provide a whole body systemic information regarding EIMD. Indeed, when muscle fibers are damaged or permeability of sarcolemma is increased, intramuscular components are released into the extracellular space and bloodstream. Therefore, the increase in level of circulating markers has been often used to quantify EIMD [10, 29]. In the present study, an increase in CK and LDH activities and Mb concentrations were observed the days after the exercises, but with different time-courses, as already reported elsewhere [30, 31]. Because CK is cleared by the reticuloendothelial system and Mb is cleared through the liver and kidney [32], differences in time-course could be different among these blood markers. Moreover, Muslimovic et al. [32] reported a new mechanism of clearance through muscle cell endocytosis that could bring a new light to this phenomenon. While we found that peak of CK activity was not necessarily larger in HIGH cluster compared to LOW and MOD clusters the hours after the exercise, we found that CK activity peaked at 24 h post-exercise for the LOW and MOD clusters and at 72 h post-exercise for the HIGH cluster. Even though CK is largely used in the literature and in clinical practice, this marker does not seem to be sensitive to EIMD in the first hours after the damaging exercise. In line with Lippi et al. [31], the time-course of changes in Mb concentration after low EIMD (LOW cluster) showed a rapid increase and return to baseline within hours (<24 h) after the exercises. However, Mb levels could remain elevated for some days after exercise after moderate to severe EIMD (MOD and HIGH). The persistent elevation in Mb and CK the days after exercise in HIGH cluster could be at least partly explained by a secondary release of the myocyte content of CK and Mb the days after the end of the exercise. Indeed, it has been reported that secondary muscle damage and fiber necrosis could occur due to the loss of Ca²⁺ homeostasis and inflammatory process [11, 33]. The time-course of blood markers could inform on the muscle state during the days after the exercise since the peak of CK activity was delayed (from 24 h to 72 h) and Mb could remain elevated and after severe EIMD. It could be that the recovery of sarcolemma integrity is dependent of the level of EIMD. This has practical implications for the diagnosis of EIMD after exercise by focusing not only on the amplitude of the blood markers but also on their time-course.

Recommendations.

Some discordance or asynchrony exists among EIMD markers. After severe EIMD (i.e., high level of MVC_{loss 24-48h}), Mb concentration peaks at 6 h post-exercice, whereas ROM and DOMS peaked at 48h and CK at 72 h post-exercise, suggesting that the presence of high level of EIMD should be highlighted by different markers as function of the timing of measurement.

Markers of force-generating capacity.

A significant correlation was found between MVC_{loss 24-48h} and evoked torque response changes at 24, 48, 72 and >96 h post-exercise (Table 2), suggesting that the amplitude of the evoked torque response could be used as a surrogate of the MVC torque without the necessity to perform maximal efforts. A significant correlation was also found between jump height loss at 24 h post-exercise and MVC_{loss 24-48h} (r² = 0.40), suggesting that jump height could be a practical, cheap and reliable alternative to evaluate the magnitude of MVC_{loss 24-48h}. (i.e., the magnitude of EIMD). However, the early changes (<6 h) of both the evoked torque response and jump height were poorly associated with MVC_{loss 24-48h} (Table 2). It is likely that early measurements of muscle function reflect the combined influence of metabolic fatigue and muscle damage [11], therefore explaining the poor correlation with the MVC_{loss 24-48h}. Indeed, while we observed a better association of MVC torque loss at <6 h with MVC_{loss 24-48h} than with early evoked response and jump height (<6 h), early MVC measurement does not seem to fully explain the observed MVC_{loss 24-48h} (r² = 0.67), likely due to metabolic/central fatigue. We found that the VAL decrease within 6 hours after exercises was associated with the MVC_{loss 24-48h}, suggesting that the (in)-ability to voluntarily activate the motor units in the early phase after the exercise could partly predict the MVC_{loss 24-48h} (i.e., indicate the magnitude of EIMD). However, early (<6 h) decrease in VAL is largely affected by muscle fatigue [38], limiting the use of this marker to predict the magnitude of MVC_{loss 24-48h}. The presence of DOMS, swelling and inflammation at 48 h post-exercise in the present study could also be involved in the reduction of VAL observed 48 h after the exercise due to the sensitivity of group III-IV afferent fibers to nociceptive and mechanical (pressure) stimuli [38]. However, our results showed that the decrease in VAL at 48 h post-exercise was small, limiting its effect on the decrease in muscle function at this time-point. RTD, a measure of the ability of the neuromuscular system to rapidly produce torque during MVC, was decreased in the first hours following exercises (<6 h), but also 48 to 96 h post-exercise. Among these time-point, only a correlation between RTD at 96 h post-exercise and MVC_{loss 24-48h} was found. Therefore, the present results were inconsistent with Penailillo et al. [25] who found that RTD at the 100–200 ms slot could be used as an early and sensitive marker of EIMD. These conflicting results could be explained by the different methods (early 0–50 vs late 100–200 ms windows) used to assess RTD. To sum up, jump height loss could be a practical, cheap and reliable alternative to evaluate the muscle function loss in EIMD context. Moreover, evoked torque response could be used as a surrogate of the MVC torque and allow to assess muscle function without the necessity to perform maximal efforts.

DOMS, ROM, and swelling.

We found that DOMS (active/passive DOMS and PPT) was poorly associated with the MVC_{loss 24-48h} (r² < 0.28), suggesting that DOMS may be a poor indicator of EIMD. On the contrary, a moderate correlation was found between ROM changes at 48 h post-exercise and the magnitude of MVC_{loss 24-48h} (r² = 0.52), suggesting that ROM may be a better indicator of magnitude of EIMD at this time point. Despite the small elevation of limb circumference, associations were found between limb circumference changes at several time points post-exercise and the magnitude of MVC_{loss 24-48h} (Table 2). This is consistent with Damas et al. [13] who found a correlation between MVC torque loss and arm circumference after eccentric exercise of the elbow flexors. Moreover, we found an association between T₂ increase at 24–48 h post-exercise and MVC_{loss 24-48h}. Thus, T₂ seems to be suitable for evaluating the EIMD only after 24 h post-exercise. Our results should nevertheless be interpreted with caution due to the small number of studies assessing limb circumference and T₂ MRI on the lower limbs.

Blood markers.

Regarding systemic indirect markers of EIMD, only Mb concentration seems to early (<6 h post-exercise) estimate the magnitude of MVC_{loss 24-48h} (Table 2). Although CK activity in blood is the most often used marker, it may not be suitable to accurately predict the magnitude of MVC_{loss 24-48h}. Indeed, this marker partly reflects the magnitude of MVC_{loss 24-48h} only 72 h post-exercise. Similarly, the lack of correlation between change in LDH activity and MVC_{loss 24-48h} suggests that LDH measurement is not useful for the evaluation of the magnitude of EIMD, likely due to the non-specificity of LDH to myocytes [39]. Despite the small to moderate increase of IL-6 concentration the days after the exercises (Fig 3), this marker was not correlated to the magnitude of MVC_{loss 24-48h}. This suggests that IL-6 concentration is not useful for the estimation of the magnitude of EIMD. These observations are consistent with those of Paulsen et al. [11] and Reihmane & Dela [40] who reported that discrepant changes in IL-6 concentrations among studies were explained by different exercise protocols and training status of the participants. Moreover, this large variability observed in the marker after eccentric exercise could be due to the various role of IL-6 in response to muscle contractions [41].

Recommendations.

Among the most common used EIMD markers, Mb concentration or MVC torque loss should be used during the first hours after the exercise (<6 h), even if these markers only partly predict the MVC_{loss 24-48h} due to high inter-individual variability and metabolic fatigue. MVC torque loss should be used beyond 24 h after the exercise, however, jump height loss and evoked torque response could be surrogates to this measure at these times points. It should be noted that ROM could be an easy and inexpensive alternative when the measure is performed 48 h after the exercise. Finally, the assessment of CK activity seems to be suitable only at 72 h post exercise to provide information on the muscle function.