Daria Neyroud

Ryanodine receptor fragmentation and sarcoplasmic reticulum Ca2+ leak after one session of high-intensity interval exercise

Significance High-intensity interval training (HIIT) has become popular because it is a time-efficient way to increase endurance. An intriguing and so-far-unanswered question is how a few minutes of HIIT can be that effective. We exposed recreationally active men to one session of three to six sets of 30-s high-intensity cycling exercise. Muscle biopsies taken 24 h later showed an extensive fragmentation of the sarcoplasmic reticulum (SR) Ca2+ channels, the ryanodine receptor 1 (RyR1). In isolated mouse muscle fibers, this fragmentation was accompanied by increased SR Ca2+ leak, which can trigger mitochondrial biogenesis. The HIIT-induced RyR1 fragmentation did not occur in muscles exposed to antioxidant, which offers an explanation for why antioxidants blunt effects of endurance training. High-intensity interval training (HIIT) is a time-efficient way of improving physical performance in healthy subjects and in patients with common chronic diseases, but less so in elite endurance athletes. The mechanisms underlying the effectiveness of HIIT are uncertain. Here, recreationally active human subjects performed highly demanding HIIT consisting of 30-s bouts of all-out cycling with 4-min rest in between bouts (≤3 min total exercise time). Skeletal muscle biopsies taken 24 h after the HIIT exercise showed an extensive fragmentation of the sarcoplasmic reticulum (SR) Ca2+ release channel, the ryanodine receptor type 1 (RyR1). The HIIT exercise also caused a prolonged force depression and triggered major changes in the expression of genes related to endurance exercise. Subsequent experiments on elite endurance athletes performing the same HIIT exercise showed no RyR1 fragmentation or prolonged changes in the expression of endurance-related genes. Finally, mechanistic experiments performed on isolated mouse muscles exposed to HIIT-mimicking stimulation showed reactive oxygen/nitrogen species (ROS)-dependent RyR1 fragmentation, calpain activation, increased SR Ca2+ leak at rest, and depressed force production due to impaired SR Ca2+ release upon stimulation. In conclusion, HIIT exercise induces a ROS-dependent RyR1 fragmentation in muscles of recreationally active subjects, and the resulting changes in muscle fiber Ca2+-handling trigger muscular adaptations. However, the same HIIT exercise does not cause RyR1 fragmentation in muscles of elite endurance athletes, which may explain why HIIT is less effective in this group.

Mechanisms of Fatigue and Task Failure Induced By Sustained Submaximal Contractions

PURPOSE The present study was designed to investigate whether central neural mechanisms limit the duration of a sustained low-force isometric contraction and the maximal force-generating capacity of the knee extensors. METHODS Fourteen healthy males (28 ± 7 yr) were asked to sustain, until voluntary exhaustion, an isometric contraction with their right knee extensor muscles at a target force equal to 20% of their maximal voluntary contraction (MVC) force. At task failure, the muscle was immediately electrically stimulated for 1 min aiming the same target force (20% MVC force). Subsequently, subjects were asked to resume the voluntary contraction for as long as possible. Knee extensor neuromuscular function was assessed before and after the entire protocol for comparison. RESULTS When electrically stimulated at the point of task failure, all subjects developed the 20% MVC force target, indicating that lack of force-generating capacity from peripheral impairment had not limited the duration of the first task. We observed a reduction in MVC force after the entire protocol (-57% ± 12%), which correlated with a decrease in potentiated peak doublet force (-48% ± 17%, P < 0.001). The level of voluntary activation, as quantified with the interpolated twitch technique, was slightly depressed after the entire protocol (from 93% ± 7% to 87% ± 10%, P < 0.01). CONCLUSIONS It follows that task failure from a sustained isometric contraction is mainly affected by central/motivational factors, whereas MVC force loss is largely explained by the extent of contractile failure of the muscle.

Comparison of neuromuscular adjustments associated with sustained isometric contractions of four different muscle groups.

The extent and characteristics of muscle fatigue of different muscle groups when subjected to a similar fatiguing task may differ. Thirteen healthy young men performed sustained contractions at 50% maximal voluntary contraction (MVC) force until task failure, with four different muscle groups, over two sessions. Per session, one upper limb and one lower limb muscle group were tested (knee extensors and thumb adductor, or plantar and elbow flexors). Changes in voluntary activation level and contractile properties were derived from doublet responses evoked during and after MVCs before and after exercise. Time to task failure differed (P < 0.05) between muscle groups (220 ± 64 s for plantar flexors, 114 ± 27 s for thumb adductor, 77 ± 25 s for knee extensors, and 72 ± 14 s for elbow flexors). MVC force loss immediately after voluntary task failure was similar (-30 ± 11% for plantar flexors, -37 ± 13% for thumb adductor, -34 ± 15% for knee extensors, and -40 ± 12% for elbow flexors, P > 0.05). Voluntary activation was decreased for plantar flexors only (from 95 ± 5% to 82 ± 9%, P < 0.05). Potentiated evoked doublet amplitude was more depressed for upper limb muscles (-59.3 ± 14.7% for elbow flexors and -60.1 ± 24.1% for thumb adductor, P < 0.05) than for knee extensors (-28 ± 15%, P < 0.05); no reduction was found in plantar flexors (-7 ± 12%, P > 0.05). In conclusion, despite different times to task failure when sustaining an isometric contraction at 50% MVC force for as long as possible, diverse muscle groups present similar loss of MVC force after task failure. Thus the extent of muscle fatigue is not affected by time to task failure, whereas this latter determines the etiology of fatigue.

Wide-pulse-high-frequency neuromuscular stimulation of triceps surae induces greater muscle fatigue compared with conventional stimulation

We compared the extent and origin of muscle fatigue induced by short-pulse-low-frequency [conventional (CONV)] and wide-pulse-high-frequency (WPHF) neuromuscular electrical stimulation. We expected CONV contractions to mainly originate from depolarization of axonal terminal branches (spatially determined muscle fiber recruitment) and WPHF contractions to be partly produced via a central pathway (motor unit recruitment according to size principle). Greater neuromuscular fatigue was, therefore, expected following CONV compared with WPHF. Fourteen healthy subjects underwent 20 WPHF (1 ms-100 Hz) and CONV (50 μs-25 Hz) evoked isometric triceps surae contractions (work/rest periods 20:40 s) at an initial target of 10% of maximal voluntary contraction (MVC) force. Force-time integral of the 20 evoked contractions (FTI) was used as main index of muscle fatigue; MVC force loss was also quantified. Central and peripheral fatigue were assessed by voluntary activation level and paired stimulation amplitudes, respectively. FTI in WPHF was significantly lower than in CONV (21,717 ± 11,541 vs. 37,958 ± 9,898 N·s P<0,001). The reductions in MVC force (WPHF: -7.0 ± 2.7%; CONV: -6.2 ± 2.5%; P < 0.01) and paired stimulation amplitude (WPHF: -8.0 ± 4.0%; CONV: -7.4 ± 6.1%; P < 0.001) were similar between conditions, whereas no change was observed for voluntary activation level (P > 0.05). Overall, our results showed a different motor unit recruitment pattern between the two neuromuscular electrical stimulation modalities with a lower FTI indicating greater muscle fatigue for WPHF, possibly limiting the presumed benefits for rehabilitation programs.

Wide-pulse-high-frequency neuromuscular electrical stimulation in cerebral palsy

OBJECTIVE The present study assesses whether wide-pulse-high-frequency (WPHF) neuromuscular electrical stimulation (NMES) could result in extra-force production in cerebral palsy (CP) patients as previously observed in healthy individuals. METHODS Ten CP and 10 age- and sex-matched control participants underwent plantar flexors NMES. Two to three 10-s WPHF (frequency: 100 Hz, pulse duration: 1 ms) and conventional (CONV, frequency 25 Hz, pulse duration: 50 μs) trains as well as two to three burst-like stimulation trains (2s at 25 Hz, 2s at 100 Hz, 2s at 25 Hz; pulse duration: 1 ms) were evoked. Resting soleus and gastrocnemii maximal H-reflex amplitude (Hmax) was normalized by maximal M-wave amplitude (Mmax) to quantify α-motoneuron modulation. RESULTS Similar Hmax/Mmax ratio was found in CP and control participants. Extra-force generation was observed both in CP (+18 ± 74%) and control individuals (+94 ± 124%) during WPHF (p<0.05). Similar extra-forces were found during burst-like stimulations in both groups (+108 ± 110% in CP and +65 ± 85% in controls, p>0.05). CONCLUSION Although the mechanisms underlying extra-force production may differ between WPHF and burst-like NMES, similar increases were observed in patients with CP and healthy controls. SIGNIFICANCE Development of extra-forces in response to WPHF NMES evoked at low stimulation intensity might open new possibilities in neuromuscular rehabilitation.

Are There Critical Fatigue Thresholds? Aggregated vs. Individual Data

The mechanisms underlying task failure from fatiguing physical efforts have been the focus of many studies without reaching consensus. An attractive but debated model explains effort termination with a critical peripheral fatigue threshold. Upon reaching this threshold, feedback from sensory afferents would trigger task disengagement from open-ended tasks or a reduction of exercise intensity of closed-ended tasks. Alternatively, the extant literature also appears compatible with a more global critical threshold of loss of maximal voluntary contraction force. Indeed, maximal voluntary contraction force loss from fatiguing exercise realized at a given intensity appears rather consistent between different studies. However, when looking at individual data, the similar maximal force losses observed between different tasks performed at similar intensities might just be an “artifact” of data aggregation. It would then seem possible that such a difference observed between individual and aggregated data also applies to other models previously proposed to explain task failure from fatiguing physical efforts. We therefore suggest that one should be cautious when trying to infer models that try to explain individual behavior from aggregated data.

Twitch potentiation induced by two different modalities of neuromuscular electrical stimulation: Implications for motor unit recruitment

Introduction: We tested the hypothesis that twitch potentiation would be greater following conventional (CONV) neuromuscular electrical stimulation (50‐µs pulse width and 25‐Hz frequency) compared with wide‐pulse high‐frequency (WPHF) neuromuscular electrical stimulation (1‐ms, 100‐Hz) and voluntary (VOL) contractions, because of specificities in motor unit recruitment (random in CONV vs. random and orderly in WPHF vs. orderly in VOL). Methods: A single twitch was evoked by means of tibial nerve stimulation before and 2 s after CONV, WPHF, and VOL conditioning contractions of the plantar flexors (intensity: 10% maximal voluntary contraction; duration: 10 s) in 13 young healthy subjects. Results: Peak twitch increased (P < 0.05) after CONV (+4.5 ± 4.0%) and WPHF (+3.3 ± 5.9%), with no difference between the 2 modalities, whereas no changes were observed after VOL (+0.8 ± 2.6%). Conclusions: Our results demonstrate that presumed differences in motor unit recruitment between WPHF and CONV do not seem to influence twitch potentiation results. Muscle Nerve 51: 412–418, 2015

Muscle Fatigue Affects the Interpolated Twitch Technique When Assessed Using Electrically-Induced Contractions in Human and Rat Muscles

The interpolated twitch technique (ITT) is the gold standard to assess voluntary activation and central fatigue. Yet, its validity has been questioned. Here we studied how peripheral fatigue can affect the ITT. Repeated contractions at submaximal frequencies were produced by supramaximal electrical stimulations of the human adductor pollicis muscle in vivo and of isolated rat soleus fiber bundles; an extra stimulation pulse was given during contractions to induce a superimposed twitch. Human muscles fatigued by repeated 30-Hz stimulation trains (3 s on–1 s off) showed an ~80% reduction in the superimposed twitch force accompanied by a severely reduced EMG response (M-wave amplitude), which implies action potential failure. Subsequent experiments combined a less intense stimulation protocol (1.5 s on–3 s off) with ischemia to cause muscle fatigue, but which preserved M-wave amplitude. However, the superimposed twitch force still decreased markedly more than the potentiated twitch force; with ITT this would reflect increased “voluntary activation.” In contrast, the superimposed twitch force was relatively spared when a similar protocol was performed in rat soleus bundles. Force relaxation was slowed by >150% in fatigued human muscles, whereas it was unchanged in rat soleus bundles. Accordingly, results similar to those in the human muscle were obtained when relaxation was slowed by cooling the rat soleus muscles. In conclusion, our data demonstrate that muscle fatigue can confound the quantification of central fatigue using the ITT.

Plantar flexor muscle weakness and fatigue in spastic cerebral palsy patients

BACKGROUND Patients with cerebral palsy develop an important muscle weakness which might affect the aetiology and extent of exercise-induced neuromuscular fatigue. AIM This study evaluated the aetiology and extent of plantar flexor neuromuscular fatigue in patients with cerebral palsy. METHODS Ten patients with cerebral palsy and 10 age- and sex-matched healthy individuals (∼20 years old, 6 females) performed four 30-s maximal isometric plantar flexions interspaced by a resting period of 2-3s to elicit a resting twitch. Maximal voluntary contraction force, voluntary activation level and peak twitch were quantified before and immediately after the fatiguing task. RESULTS Before fatigue, patients with cerebral palsy were weaker than healthy individuals (341±134N vs. 858±151N, p<0.05) and presented lower voluntary activation (73±19% vs. 90±9%, p<0.05) and peak twitch (100±28N vs. 199±33N, p<0.05). Maximal voluntary contraction force was not significantly reduced in patients with cerebral palsy following the fatiguing task (-10±23%, p>0.05), whereas it decreased by 30±12% (p<0.05) in healthy individuals. CONCLUSIONS Plantar flexor muscles of patients with cerebral palsy were weaker than their healthy peers but showed greater fatigue resistance. WHAT THIS PAPER ADDS Cerebral palsy is a widely defined pathology that is known to result in muscle weakness. The extent and origin of muscle weakness were the topic of several previous investigations; however some discrepant results were reported in the literature regarding how it might affect the development of exercise-induced neuromuscular fatigue. Importantly, most of the studies interested in the assessment of fatigue in patients with cerebral palsy did so with general questionnaires and reported increased levels of fatigue. Yet, exercise-induced neuromuscular fatigue was quantified in just a few studies and it was found that young patients with cerebral palsy might be more fatigue resistant that their peers. Thus, it appears that (i) conflicting results exist regarding objectively-evaluated fatigue in patients with cerebral palsy and (ii) the mechanisms underlying this muscle fatigue - in comparison to those of healthy peers - remain poorly understood. The present study adds important knowledge to the field as it shows that when young adults with cerebral palsy perform sustained maximal isometric plantar flexions, they appear less fatigable than healthy peers. This difference can be ascribed to a better preservation of the neural drive to the muscle. We suggest that the inability to drive their muscles maximally accounts for the lower extent of exercise-induced neuromuscular fatigue in patients with cerebral palsy.

Commentaries on Viewpoint: Inappropriate interpretation of surface EMG signals and muscle fiber characteristics impedes understanding of the control of neuromuscular function

to the editor: Enoka and Duchateau ([2][1]) correctly call for caution when interpreting voluntary surface electromyography (sEMG) in terms of neural drive. If voluntary sEMG signals recorded during nonfatiguing isometric contractions depend on the number of motor units recruited, their firing rate