Role of macrophages during skeletal muscle regeneration and hypertrophy-Implications for immunomodulatory strategies.

Skeletal muscle is a plastic tissue that regenerates ad integrum after injury and adapts to raise mechanical loading/contractile activity by increasing its mass and/or myofiber size, a phenomenon commonly refers to as skeletal muscle hypertrophy. Both muscle regeneration and hypertrophy rely on the interactions between muscle stem cells and their neighborhood, which include inflammatory cells, and particularly macrophages. This review first summarizes the role of macrophages in muscle regeneration in various animal models of injury and in response to exercise-induced muscle damage in humans. Then, the potential contribution of macrophages to skeletal muscle hypertrophy is discussed on the basis of both animal and human experiments. We also present a brief comparative analysis of the role of macrophages during muscle regeneration versus hypertrophy. Finally, we summarize the current knowledge on the impact of different immunomodulatory strategies, such as heat therapy, cooling, massage, nonsteroidal anti-inflammatory drugs and resolvins, on skeletal muscle regeneration and their potential impact on muscle hypertrophy.

Effects of Neuromuscular Electrical Stimulation on Quadriceps Muscle Strength and Mass in Healthy Young and Older Adults: A Scoping Review.

OBJECTIVE: Although neuromuscular electrical stimulation (NMES) has been used as a safe and relevant complement to voluntary resistance training, its effectiveness in increasing quadriceps femoris muscle strength and mass in healthy young and older adults has not been determined. The aim of this scoping review was to assess the effects of NMES on quadriceps muscle strength and mass in healthy young and older adults. METHODS: CENTRAL, Pedro, MEDLINE, and PubMed were searched from inception to September 2019. Randomized controlled trials (RCTs) that compared NMES with control group or voluntary resistance training for healthy young and older adults were included. Study characteristics, primary and secondary outcome parameters, and details of the NMES intervention were extracted by 2 reviewers. Only studies for which full text was available in English were included. RESULTS: Thirty-two RCTs including 796 healthy participants were identified as being eligible for young adults, and 5 RCTs including 123 healthy participants were identified as being eligible for older adults. The available evidence strongly suggests that NMES improves quadriceps muscle strength compared with a control group in young adults, but its efficacy seems lower than that of voluntary resistance training. The available limited evidence regarding the effects of NMES on quadriceps muscle mass compared with control in young adults is inconclusive, with 3 RCTs showing positive effects and 3 RCTs not showing positive effects. The very limited available evidence from 5 RCTs in older adults suggests that NMES might be beneficial for increasing quadriceps muscle strength and mass. CONCLUSION: Overall, the evidence indicates that NMES is an efficacious method for increasing quadriceps muscle strength in young adults, whereas its impact on muscle mass requires further investigations. In addition, the effectiveness of NMES needs to be confirmed in older adults on the basis of more high-quality RCTs with larger sample sizes. IMPACT: This scoping review of 37 RCTs including 919 people is the first study, to the authors' knowledge, to show that the use of NMES increases quadriceps muscle strength in young adults and might improve quadriceps muscle strength compared with control interventions in older adults. In both young and older adults, the effects of NMES on quadriceps muscle mass are still unclear.

Muscle alterations induced by electrostimulation are lower at short quadriceps femoris length.

PURPOSE: This study aimed at determining through MRI investigations, force and soreness assessments whether the modulation of muscle length is a relevant strategy for minimising neuromuscular electrical stimulation (NMES)-induced muscle damage in young healthy participants. METHODS: Comparison of 2 NMES sessions (40 isometric electrically-evoked contractions of the knee extensors) was randomly performed on 1 knee flexed at 50° (short muscle length) and the contralateral at 100° (long muscle length) in a single group of healthy participants. Indirect markers of muscle damage including changes in maximal voluntary isometric contraction (MVC) force, muscle volume and transverse relaxation time (T2) were measured before, 2 days (D2), 4 days (D4) and 7 days (D7) after the NMES sessions in each limb of the ten participants. RESULTS: Although stimulation intensity was similar during the NMES session on both limbs, significantly lower force production was recorded at long muscle length (peak at 30 ± 5% MVC force) as compared to short muscle length (peak at 61 ± 12% MVC force). In the following days, MVC force at long muscle length was decreased from D2 to D7, whereas no significant change occurred at short muscle length. Increases in muscle volume and T2 were found at each time point in stimulated muscles at long muscle length, whereas no change was found at short muscle length. CONCLUSION: For the same stimulation intensity, NMES-induced isometric contractions generate higher knee extension force output and result in lower muscle tissues alterations that could be related to a lower intramuscular shear strain when exercise is performed at short muscle length.

Spatial difference can occur between activated and damaged muscle areas following electrically-induced isometric contractions.

KEY POINTS: T2 mapping combined to image registration and statistical parametric mapping analysis is a suitable methodology to accurately localize and compare the extent of both activated and damaged muscle areas. Activated muscle areas following electrically-induced isometric contractions are superficial, but damaged regions are muscle specific and can be related to the muscle morphology and/or the relative spatial position within a muscle group leading to potential intramuscular muscle shear strain. Tissues other than active skeletal muscle fibres can be altered during unaccustomed neuromuscular electrical stimulation-induced isometric contractions. ABSTRACT: Skeletal muscle isometric contractions induced by neuromuscular electrical stimulation (NMES) exercise can generate damage within activated muscles. This study aimed at comparing the localization and the extent of NMES-activated muscle areas and induced damage regions using magnetic resonance imaging. Thirteen healthy subjects performed a single bout of NMES-induced isometric contractions known to induce a decrease in maximal voluntary isometric contraction (MVC) and increase in muscle volume and transverse relaxation time (T2 ). All the parameters were measured before, immediately after (POST), 7 days (D7), 14 days (D14) and 21 days (D21) after the NMES session. Spatial normalization of T2 maps were performed to compare the localization of muscle activation areas and damaged muscle regions from statistical mapping analyses. A significant decrease in MVC was found at POST (-26 ± 9%) and in delayed time at D7 (-20 ± 6%) and D14 (-12 ± 5%). Although muscle activation was statistically detected through T2 increase at POST in superficial parts of the two muscles located beneath the stimulation electrodes (i.e. vastus lateralis and vastus medialis), alterations quantified in a delayed time from increased T2 were mainly located in the deep muscle region of the vastus lateralis (+57 ± 24% of mean T2 ) and superficial area of the vastus medialis (+24 ± 16% of mean T2 ) at D7 and were still observed in whole muscle at D21. The discrepancy between activated and damaged areas in the vastus lateralis implies that tissues other than active skeletal muscle fibres were altered during unaccustomed NMES-induced isomeric contractions.

L-tyrosine supplementation does not ameliorate skeletal muscle dysfunction in zebrafish and mouse models of dominant skeletal muscle α-actin nemaline myopathy.

L-tyrosine supplementation may provide benefit to nemaline myopathy (NM) patients, however previous studies are inconclusive, with no elevation of L-tyrosine levels in blood or tissue reported. We evaluated the ability of L-tyrosine treatments to improve skeletal muscle function in all three published animal models of NM caused by dominant skeletal muscle α-actin (ACTA1) mutations. Highest safe L-tyrosine concentrations were determined for dosing water and feed of wildtype zebrafish and mice respectively. NM TgACTA1D286G-eGFP zebrafish treated with 10 µM L-tyrosine from 24 hours to 6 days post fertilization displayed no improvement in swimming distance. NM TgACTA1D286G mice consuming 2% L-tyrosine supplemented feed from preconception had significant elevations in free L-tyrosine levels in sera (57%) and quadriceps muscle (45%) when examined at 6-7 weeks old. However indicators of skeletal muscle integrity (voluntary exercise, bodyweight, rotarod performance) were not improved. Additionally no benefit on the mechanical properties, energy metabolism, or atrophy of skeletal muscles of 6-7 month old TgACTA1D286G and KIActa1H40Y mice eventuated from consuming a 2% L-tyrosine supplemented diet for 4 weeks. Therefore this study yields important information on aspects of the clinical utility of L-tyrosine for ACTA1 NM.

Clinical Use of Neuromuscular Electrical Stimulation for Neuromuscular Rehabilitation: What Are We Overlooking?

The clinical success of neuromuscular electrical stimulation (NMES) for neuromuscular rehabilitation is greatly compromised by the poor consideration of different physiological and methodological issues that are not always obvious to the clinicians. Therefore, the aim of this narrative review is to reexamine some of these fundamental aspects of NMES using a tripartite model perspective. First, we contend that NMES does not actually bypass the central nervous system but results in a multitude of neurally mediated responses that contribute substantially to force generation and may engender neural adaptations. Second, we argue that too much emphasis is generally placed on externally controllable stimulation parameters while the major determinant of NMES effectiveness is the intrinsically determined muscle tension generated by the current (ie, evoked force). Third, we believe that a more systematic approach to NMES therapy is required in the clinic and this implies a better identification of the patient-specific impairment and of the potential "responders" to NMES therapy. On the basis of these considerations, we suggest that the crucial steps to ensure the clinical effectiveness of NMES treatment should consist of (1) identifying the neuromuscular impairment with clinical assessment and (2) implementing algorithm-based NMES therapy while (3) properly dosing the treatment with tension-controlled NMES and eventually amplifying its neural effects.

Specific brain activation patterns associated with two neuromuscular electrical stimulation protocols.

The influence of neuromuscular electrical stimulation (NMES) parameters on brain activation has been scarcely investigated. We aimed at comparing two frequently used NMES protocols - designed to vary in the extent of sensory input. Whole-brain functional magnetic resonance imaging was performed in sixteen healthy subjects during wide-pulse high-frequency (WPHF, 100 Hz-1 ms) and conventional (CONV, 25 Hz-0.05 ms) NMES applied over the triceps surae. Each protocol included 20 isometric contractions performed at 10% of maximal force. Voluntary plantar flexions (VOL) were performed as control trial. Mean force was not different among the three protocols, however, total current charge was higher for WPHF than for CONV. All protocols elicited significant activations of the sensorimotor network, cerebellum and thalamus. WPHF resulted in lower deactivation in the secondary somatosensory cortex and precuneus. Bilateral thalami and caudate nuclei were hyperactivated for CONV. The modulation of the NMES parameters resulted in differently activated/deactivated regions related to total current charge of the stimulation but not to mean force. By targeting different cerebral brain regions, the two NMES protocols might allow for individually-designed rehabilitation training in patients who can no longer execute voluntary movements.

Effects of branched-chain amino acids supplementation on both plasma amino acids concentration and muscle energetics changes resulting from muscle damage: A randomized placebo controlled trial.

BACKGROUND & AIMS: Branched-chain amino acids promote muscle-protein synthesis, reduce protein oxidation and have positive effects on mitochondrial biogenesis and reactive oxygen species scavenging. The purpose of the study was to determine the potential benefits of branched-chain amino acids supplementation on changes in force capacities, plasma amino acids concentration and muscle metabolic alterations after exercise-induced muscle damage. METHODS: (31)P magnetic resonance spectroscopy and biochemical analyses were used to follow the changes after such damage. Twenty six young healthy men were randomly assigned to supplemented branched-chain amino acids or placebo group. Knee extensors maximal voluntary isometric force was assessed before and on four days following exercise-induced muscle damage. Concentrations in phosphocreatine [PCr], inorganic phosphate [Pi] and pH were measured during a standardized rest-exercise-recovery protocol before, two (D2) and four (D4) days after exercise-induced muscle damage. RESULTS: No significant difference between groups was found for changes in maximal voluntary isometric force (-24% at D2 and -21% at D4). Plasma alanine concentration significantly increased immediately after exercise-induced muscle damage (+25%) in both groups while concentrations in glycine, histidine, phenylalanine and tyrosine decreased. No difference between groups was found in the increased resting [Pi] (+42% at D2 and +34% at D4), decreased resting pH (-0.04 at D2 and -0.03 at D4) and the slower PCr recovery rate (-18% at D2 and -24% at D4). CONCLUSIONS: The damaged muscle was not able to get benefits out of the increased plasma branched-chain amino acids availability to attenuate changes in indirect markers of muscle damage and muscle metabolic alterations following exercise-induced muscle damage.

Impaired mitochondrial function and reduced energy cost as a result of muscle damage.

PURPOSE: Although it has been largely acknowledged that isometric neuromuscular electrostimulation (NMES) exercise induces larger muscle damage than voluntary contractions, the corresponding effects on muscle energetics remain to be determined. Voluntary exercise-induced muscle damage (EIMD) has been reported to have minor slight effects on muscle metabolic response to subsequent dynamic exercise, but the magnitude of muscle energetics alterations for NMES EIMD has never been documented. METHODS: ³¹P magnetic resonance spectroscopy measurements were performed in 13 young healthy males during a standardized rest-exercise-recovery protocol before (D0) and 2 d (D2) and 4 d (D4) after NMES EIMD on knee extensor muscles. Changes in kinetics of phosphorylated metabolite concentrations (i.e., phosphocreatine [PCr], inorganic phosphate [Pi], and adenosine triphosphate [ATP]) and pH were assessed to investigate aerobic and anaerobic rates of ATP production and energy cost of contraction (Ec). RESULTS: Resting [Pi]/[PCr] ratio increased at D2 (+39%) and D4 (+29%), mainly owing to the increased [Pi] (+43% and +32%, respectively), whereas a significant decrease in resting pH was determined (-0.04 pH unit and -0.03 pH unit, respectively). PCr recovery rate decreased at D2 (-21%) and D4 (-23%) in conjunction with a significantly decreased total rate of ATP production at D4 (-18%) mainly owing to an altered aerobic ATP production (-19%). Paradoxically, Ec was decreased at D4 (-21%). CONCLUSION: Overall, NMES EIMD led to intramuscular acidosis in resting muscle and mitochondrial impairment in exercising muscle. Alterations of noncontractile processes and/or adaptive mechanisms to muscle damage might account for the decreased Ec during the dynamic exercise.

Heterogeneity of muscle damage induced by electrostimulation: a multimodal MRI study.

PURPOSE: Neuromuscular electrostimulation (NMES) leads to a spatially fixed, synchronous, and superficial motor unit recruitment, which could induce muscle damage. Therefore, the extent of muscle damage and its spatial occurrence were expected to be heterogeneous across and along the quadriceps femoris (QF) muscles. The aim of the present study was to characterize muscle spatial heterogeneity in QF damage after a single bout of isometric NMES using multimodal magnetic resonance imaging (MRI). METHODS: Twenty-five young healthy males participated in this study. MRI investigations consisted of the assessment of muscle volume, transverse relaxation time (T2), and diffusion tensor imaging (DTI) in muscles positioned near the stimulation electrodes (i.e., vastus lateralis (VL) and vastus medialis (VM)) and muscles located outside the stimulated regions (i.e., vastus intermedius and rectus femoris). These measurements were performed 6 d before, and 2 d and 4 d (D4) after the NMES session. RESULTS: For the muscles placed in direct contact with the stimulation electrodes, volume (VL, +8.5%; VM, +3.8%), T2 (VL, +19.5%; VM, +6.7%) and radial diffusivity (λ3) (VL, + 7.3%; VM, +3.7%) significantly increased at D4. Whereas MRI parameter changes were larger for VL as compared with those for other QF muscles at D4, homogeneous alterations were found along all QF muscles. CONCLUSIONS: Isometric NMES induced specific and localized alterations in VL and VM, with heterogeneous damage amplitude among them. Potential effects of unaccustomed intermuscle shear stress during electrically evoked isometric contractions could be a key factor in the spatial occurrence and the extent of damage among QF muscles (especially in VL). The kinetics and extent of MRI changes varied between T2 and diffusion tensor imaging metrics, suggesting the involvement of different physiological processes.

Time course of central and peripheral alterations after isometric neuromuscular electrical stimulation-induced muscle damage.

Isometric contractions induced by neuromuscular electrostimulation (NMES) have been shown to result in a prolonged force decrease but the time course of the potential central and peripheral factors have never been investigated. This study examined the specific time course of central and peripheral factors after isometric NMES-induced muscle damage. Twenty-five young healthy men were subjected to an NMES exercise consisting of 40 contractions for both legs. Changes in maximal voluntary contraction force of the knee extensors (MVC), peak evoked force during double stimulations at 10 Hz (Db(10)) and 100 Hz (Db(100)), its ratio (10:100), voluntary activation, muscle soreness and plasma creatine kinase activity were assessed before, immediately after and throughout four days after NMES session. Changes in knee extensors volume and T2 relaxation time were also assessed at two (D2) and four (D4) days post-exercise. MVC decreased by 29% immediately after NMES session and was still 19% lower than the baseline value at D4. The decrease in Db(10) was higher than in Db(100) immediately and one day post-exercise resulting in a decrease (-12%) in the 10:100 ratio. On the contrary, voluntary activation significantly decreased at D2 (-5%) and was still depressed at D4 (-5%). Muscle soreness and plasma creatine kinase activity increased after NMES and peaked at D2 and D4, respectively. T2 was also increased at D2 (6%) and D4 (9%). Additionally, changes in MVC and peripheral factors (e.g., Db(100)) were correlated on the full recovery period, while a significant correlation was found between changes in MVC and VA only from D2 to D4. The decrease in MVC recorded immediately after the NMES session was mainly due to peripheral changes while both central and peripheral contributions were involved in the prolonged force reduction. Interestingly, the chronological events differ from what has been reported so far for voluntary exercise-induced muscle damage.

Neuromuscular electrical stimulation training induces atypical adaptations of the human skeletal muscle phenotype: a functional and proteomic analysis.

The aim of the present study was to define the chronic effects of neuromuscular electrical stimulation (NMES) on the neuromuscular properties of human skeletal muscle. Eight young healthy male subjects were subjected to 25 sessions of isometric NMES of the quadriceps muscle over an 8-wk period. Needle biopsies were taken from the vastus lateralis muscle before and after training. The training status, myosin heavy chain (MHC) isoform distribution, and global protein pattern, as assessed by proteomic analysis, widely varied among subjects at baseline and prompted the identification of two subgroups: an "active" (ACT) group, which performed regular exercise and had a slower MHC profile, and a sedentary (SED) group, which did not perform any exercise and had a faster MHC profile. Maximum voluntary force and neural activation significantly increased after NMES in both groups (+∼30% and +∼10%, respectively). Both type 1 and 2 fibers showed significant muscle hypertrophy. After NMES, both groups showed a significant shift from MHC-2X toward MHC-2A and MHC-1, i.e., a fast-to-slow transition. Proteomic maps showing ∼500 spots were obtained before and after training in both groups. Differentially expressed proteins were identified and grouped into functional categories. The most relevant changes regarded 1) myofibrillar proteins, whose changes were consistent with a fast-to-slow phenotype shift and with a strengthening of the cytoskeleton; 2) energy production systems, whose changes indicated a glycolytic-to-oxidative shift in the metabolic profile; and 3) antioxidant defense systems, whose changes indicated an enhancement of intracellular defenses against reactive oxygen species. The adaptations in the protein pattern of the ACT and SED groups were different but were, in both groups, typical of both resistance (i.e., strength gains and hypertrophy) and endurance (i.e., a fast-to-slow shift in MHC and metabolic profile) training. These training-induced adaptations can be ascribed to the peculiar motor unit recruitment pattern associated with NMES.

Effects of stimulation frequency and pulse duration on fatigue and metabolic cost during a single bout of neuromuscular electrical stimulation.

We have investigated the effects of stimulation frequency and pulse duration on fatigue and energy metabolism in rat gastrocnemius muscle during a single bout of neuromuscular electrical stimulation (NMES). Electrical pulses were delivered at 100 Hz (1-ms pulse duration) and 20 Hz (5-ms pulse duration) for the high (HF) and low (LF) frequency protocols, respectively. As a standardization procedure, the averaged stimulation intensity, the averaged total charge, the initial peak torque, the duty cycle, the contraction duration and the torque-time integral were similar in both protocols. Fatigue was assessed using two testing trains delivered at a frequency of 100 Hz and 20 Hz before and after each protocol. Metabolic changes were investigated in vivo using 31P-magnetic resonance spectroscopy (31P-MRS) and in vitro in freeze-clamped muscles. Both LF and HF NMES protocols induced the same decrease in testing trains and metabolic changes. We conclude that, under carefully controlled and comparable conditions, the use of low stimulation frequency and long pulse duration do not minimize the occurrence of muscle fatigue or affect the corresponding stimulation-induced metabolic changes so that this combination of stimulation parameters would not be adequate in the context of rehabilitation.

Effect of electrostimulation training-detraining on neuromuscular fatigue mechanisms.

The aim of this study was to evaluate the effects of neuromuscular electrical stimulation (NMES) training and subsequent detraining on neuromuscular fatigue mechanisms. Ten young healthy men completed one NMES fatigue protocol before and after a NMES training program of 4 weeks and again after 4 weeks of detraining. Muscle fatigue (maximal voluntary torque loss), central fatigue (activation failure), and peripheral fatigue (transmission failure and contractile failure) of the plantar flexor muscles were assessed by using a series of electrically evoked and voluntary contractions with concomitant electromyographic and torque recordings. At baseline, maximal voluntary torque decreased significantly with fatigue (P<0.001), due to both activation and transmission failure. After detraining, maximal voluntary torque loss was significantly reduced (P<0.05). In the same way, the relative decrease in muscle activation after training and detraining was significantly lower compared to baseline values (P<0.05). Short-term NMES training-detraining of the plantar flexor muscles significantly reduced the muscle fatigue associated to one single NMES exercise session. This was mainly attributable to a reduction in activation failure, i.e., lower central fatigue, probably as a result of subject's accommodation to pain and discomfort during NMES.

Late neural adaptations to electrostimulation resistance training of the plantar flexor muscles.

The present study aimed to examine early and late neural adaptations to short-term electrostimulation training of the plantar flexor muscles. Changes in triceps surae muscle activation (twitch interpolation), maximal electromyographic (EMG) activity, H-reflex amplitudes and antagonist coactivation were investigated after electrostimulation training (4 weeks) and after 4 weeks of detraining in a group of ten young healthy men. Maximal voluntary contraction torque was significantly higher (P < 0.01) after training (+19.4%) and detraining (+17.2%) with respect to baseline. Activation level, soleus and lateral gastrocnemius EMG normalized to the maximal M-wave significantly increased as a result of training (P < 0.05), and these gains were preserved after detraining, excepted for soleus EMG. Maximal H reflex to maximal M wave ratio increased significantly between baseline and detraining for both soleus and lateral gastrocnemius muscles (P < 0.05). Tibialis anterior coactivation was unchanged after training but significantly decreased after the detraining period (P < 0.01). Short-term electrostimulation resistance training was accompanied by early (increased muscle activation and EMG activity) and late neural adaptations (increased spinal reflex amplitude and decreased coactivation), likely explaining the increase and then the preservation of the maximal voluntary strength. These effects may help in conceiving and programming effective electrostimulation therapy programs for both healthy and immobilized plantar flexor muscles.

Central and peripheral contributions to fatigue after electrostimulation training.

PURPOSE: We examined the effect of 4 (WK4) and 8 wk (WK8) of neuromuscular electrical stimulation (NMES) training on both endurance time and mechanisms contributing to task failure. METHODS: Ten males performed a fatiguing isometric contraction with the knee extensor muscles at 20% of maximal voluntary contraction (MVC) until exhaustion before (B), at WK4, and at WK8 of NMES training. The electromyographic (EMG) activity and muscle activation obtained under MVC were recorded before and after the fatiguing task to assess central fatigue. Torque and EMG responses obtained under electrically evoked contractions were examined before and after the fatiguing task to analyze peripheral fatigue. RESULTS: Knee extensor MVC torque increased significantly between B and WK4 (+16%), between WK4 and WK8 (+10%), and between B and WK8 (+26%), which meant that the average target torque sustained during the fatiguing contraction increased between the testing sessions. Endurance time decreased significantly over the three sessions (493+/-101 s at B, 408+/-159 s at WK4, and 338+/-126 s at WK8) despite a similar reduction in knee extensor MVC (approximately 25%). Negative correlations were found between endurance time absolute changes and target torque absolute gains. Average EMG activity of the knee extensor muscles was lower after training, but the mean rate of increase was similar over the three sessions. Single-twitch contractile properties were not affected by the task. CONCLUSION: We conclude that the endurance time was shorter after 4 and 8 wk of NMES training, and this was associated with higher absolute contraction intensity. Despite endurance time reduction, NMES training did not affect the amount of fatigue at exhaustion nor the central and peripheral contributions to fatigue.

Neural and muscular changes to detraining after electrostimulation training.

We investigated the effects of 4 weeks of detraining subsequent to an 8-week electrostimulation (ES) training program on changes in muscle strength, neural and muscular properties of the knee extensor muscles. Nine male subjects followed the training program consisting of 32 sessions of isometric ES training over an 8-week period. All subjects were tested before and after 8 weeks of ES training, and were then retested after 4 weeks of detraining. Quadriceps muscle anatomical cross-sectional area (ACSA) was assessed by ultrasonography imaging. The electromyographic (EMG) activity and muscle activation (i.e., by means of the twitch interpolation technique) obtained during maximal voluntary contractions (MVC) were used to examine neural adaptations. After training, the knee extensor voluntary torque increased significantly by 26%. Torque gains were accompanied by an increase in vastii EMG activity normalized to respective M-wave (+43%), muscle activation (+6%) and quadriceps ACSA (+6%). After detraining, knee extensor MVC, vastii EMG activity, muscle activation and quadriceps ACSA decreased significantly by 9%, 20%, 5% and 3%, respectively. Also, the knee extensor MVC values remained significantly elevated (14%) above baseline levels at the end of the detraining period and this was associated with a larger quadriceps ACSA (+3%) but not with a higher neural activation. We concluded that the voluntary torque losses observed after detraining could be attributed to both neural and muscular alterations. Muscle size preservation could explain the higher knee extensor MVC values observed after the cessation of training compared to those obtained before training, therefore indicating that muscle size changes are slower than neural drive reduction.