To help reduce the gap between the cellular physiology of motoneurons (MNs) as studied "bottom-up" in animal preparations and the "top-down" study of the firing patterns of human motor units (MUs), this article addresses the question of whether motoneuron adaptation contributes to muscle fatigue. Findings are reviewed on the intracellularly recorded electrophysiology of spinal MNs as studied in vivo and in vitro using animal preparations, and the extracellularly recorded discharge of MUs as studied in conscious humans. The latter "top-down" approach, combined with kinetic measurements, has provided most of what is currently known about the neurobiology of muscle fatigue, including its task and context dependencies. It is argued that although the question addressed is still open, it should now be possible to design new "bottom-up" research paradigms using animal preparations that take advantage of what has been learned with the use of relatively noninvasive quantitative procedures in conscious humans.

The present study examined functional connectivity (FC) between functional MRI (fMRI) signals of the primary motor cortex (M1) and each of the three subcortical neural structures, cerebellum (CB), basal ganglia (BG), and thalamus (TL), during muscle fatigue using the quantile regression technique. Understanding activation relation between the subcortical structures and the M1 during prolonged motor performance should help delineate how central motor control network modulates acute perturbations at peripheral sensorimotor system such as muscle fatigue. Ten healthy subjects participated in the study and completed a 20-minute intermittent handgrip motor task at 50% of their maximal voluntary contraction (MVC) level. Quantile regression analyses were carried out to compare the FC between the contralateral (left) M1 and CB, BG, and TL in the minimal (beginning 100 s) versus significant (ending 100 s) fatigue stages. Widespread, statistically significant increases in FC were found in bilateral BG, CB, and TL with the left M1 during significant versus minimal fatigue stages. Our results imply that these subcortical nuclei are critical components in the motor control network and actively involved in modulating voluntary muscle fatigue, possibly, by working together with the M1 to strengthen the descending central command to prolong the motor performance.

Carbonic anhydrase III (CAIII) is expressed abundantly in slow skeletal muscles, adipocytes, and the liver. It plays a critical role in maintaining intracellular pH, antioxidation, and energy metabolism, which are further involved in fatigue. However, its function and mechanism in maintaining the physiological function of muscles or antifatigue are still ambiguous. We hypothesized that changes of CAIII in skeletal muscles might be related to the occurrence of muscle fatigue.

Muscle fatigue is a temporary decline in the force and power capacity of skeletal muscle resulting from muscle activity. Because control of muscle is realized at the level of the motor unit (MU), it seems important to consider the physiological properties of motor units when attempting to understand and predict muscle fatigue. Therefore, we developed a phenomenological model of motor unit fatigue as a tractable means to predict muscle fatigue for a variety of tasks and to illustrate the individual contractile responses of MUs whose collective action determines the trajectory of changes in muscle force capacity during prolonged activity. An existing MU population model was used to simulate MU firing rates and isometric muscle forces and, to that model, we added fatigue-related changes in MU force, contraction time, and firing rate associated with sustained voluntary contractions. The model accurately estimated endurance times for sustained isometric contractions across a wide range of target levels. In addition, simulations were run for situations that have little experimental precedent to demonstrate the potential utility of the model to predict motor unit fatigue for more complicated, real-world applications. Moreover, the model provided insight into the complex orchestration of MU force contributions during fatigue, that would be unattainable with current experimental approaches.

Several inherited disorders involve chronic fatigue, muscle weakness and pain. These conditions can depend on muscle, nerve, brain, metabolic and mitochondrial defects. A major trigger of muscle weakness and fatigue is exercise. The amount of exercise that triggers symptoms and the frequency of symptoms are highly variable. In this review, the genetic causes and molecular pathways involved in these disorders are discussed along with the diagnostic and treatment options available, with the aim of fostering understanding of the disease and exploring therapeutic options.

Fatigue caused by sustaining submaximal-intensity muscle contraction(s) involves increased activation in the brain such as primary motor cortex (M1), primary sensory cortex (S1), premotor and supplementary motor area (PM&SMA) and prefrontal cortex (PFC). The synchronized increases in activation level in these cortical areas suggest fatigue-related strengthening of functional coupling within the motor control network. In the present study, this hypothesis was tested using the cross-correlation based functional connectivity (FC) analysis method. Ten subjects performed a 20-minute intermittent (3.5s ON/6.5s OFF, 120 trials total) handgrip task using the right hand at 50% maximal voluntary contraction (MVC) force level while their brain was scanned by a 3 T Siemens Trio scanner using echo planar imaging (EPI) sequence. A representative signal time course of the left M1 was extracted by averaging the time course data of a 2-mm cluster of neighboring voxels of local maximal activation foci, which was identified by a general linear model. Two FC activation maps were created for each subject by cross-correlating the time course data of the minimal (the first 10 trials) and significant (the last 10 trials) fatigue stages across all the voxels in the brain to the corresponding representative time course. Histogram and quantile regression analysis were used to compare the FC between the minimal and significant fatigue stages and the results showed a significant increase in FC among multiple cortical regions, including right M1 and bilateral PM&SMA, S1 and PFC. This strengthened FC indicates that when muscle fatigue worsens, many brain regions increase their coupling with the left M1, the primary motor output control center for the right handgrip, to compensate for diminished force generating capability of the muscle in a coordinated fashion by enhancing the descending command for greater muscle recruitment to maintain the same force.

Muscle fatigue has been known to influence brain activity, but very little is known about how cortical centers respond to muscle fatigue.

In experiments on small bundles of intact fibers from a rat fast muscle, in vitro, we examined the decline in force in repeated tetanic contractions; the aim was to characterize the effect of shortening and of temperature on the initial phase of muscle fatigue. Short tetanic contractions were elicited at a control repetition rate of 1/60 s, and fatigue was induced by raising the rate to 1/5 s for 2-3 min, both in isometric mode (no shortening) and in shortening mode, in which each tetanic contraction included a ramp shortening at a standard velocity. In experiments at 20 degrees C (n = 12), the force decline during a fatigue run was 25% in the isometric mode but was significantly higher (35%) in the shortening mode. In experiments at different temperatures (10-30 degrees C, n = 11), the tetanic frequency and duration were adjusted as appropriate, and for shortening mode, the velocity was adjusted for maximum power output. In isometric mode, fatigue of force was significantly less at 30 degrees C ( approximately 20%) than at 10 degrees C ( approximately 30%); the power output (force x velocity) was >10x higher at 30 degrees C than at 10 degrees C, and power decline during a fatigue run was less at 30 degrees C ( approximately 20-30%) than at 10 degrees C ( approximately 50%). The finding that the extent of fatigue is increased with shortening contractions and is lower at higher temperatures is consistent with the view that force depression by inorganic phosphate, which accumulates within fibers during activity, may be a primary cause of initial muscle fatigue.

As a common neurophysiological phenomenon, voluntary muscle fatigue is accompanied by changes in both the central nervous system and peripheral muscles. Considering the effectiveness of the muscle network and the functional corticomuscular coupling (FCMC) in analyzing motor function, muscle fatigue can be analyzed by quantitating the intermuscular coupling and corticomuscular coupling. However, existing coherence-based research on muscle fatigue are limited by the inability of the coherence algorithm to identify the coupling direction, which cannot further reveal the underlying neural mechanism of muscle fatigue. To address this problem, we applied the time-delayed maximal information coefficient (TDMIC) method to quantitate the directional informational interaction in the muscle network and FCMC during a right-hand stabilized grip task. Eight healthy subjects were recruited to the present study. For the muscle networks, the beta-band information flow increased significantly due to muscle fatigue, and the information flow between the synergist muscles were stronger than that between the synergist and antagonist muscles. The information flow in the muscle network mainly flows to flexor digitorum superficialis (FDS), flexor carpi ulnar (FCU), and brachioradialis (BR). For the FCMC, muscle fatigue caused a significant decrease in the beta- and gamma-band bidirectional information flow. Further analysis revealed that the beta-band information flow was significantly stronger in the descending direction [electroencephalogram (EEG) to surface electromyography (sEMG)] than that in the ascending direction (sEMG to EEG) during pre-fatigue tasks. After muscle fatigue, the beta-band information flow in the ascending direction was significantly stronger than that in the descending direction. The present study demonstrates the influence of muscle fatigue on information flow in muscle networks and FCMC. We proposes that beta-band intermuscular and corticomuscular informational interaction plays an adjusting role in autonomous movement completion under muscle fatigue. Directed information flow analysis can be used as an effective method to explore the neural mechanism of muscle fatigue on the macroscopic scale.

We tested the hypothesis that muscle fatigue would attenuate vasodilatory responsiveness throughout the resistance network. The retractor muscle of anaesthetized hamsters was contracted (once per 2 s for 1 min) at duty cycles of 2.5, 10 and 20 % before and after fatiguing contractions that diminished peak tension and muscle glycogen by >50 %. Arterioles and feed arteries (FA) dilated maximally during fatiguing contractions. Resting vasomotor tone consistently recovered following contractions. Peak blood flow was proportional to integrated tension (tension x time, expressed in mN mm-2 s); both increased with duty cycle and decreased with fatigue. Total integrated vasodilatory responses (diameter x time, expressed in microm s) increased with duty cycle and decreased with fatigue. Vasodilatation during contractions plateaued at approximately 50 % of peak integrated tension. Post-contraction vasodilatation increased with integrated tension and both were attenuated with fatigue. As integrated tension increased, distal arterioles dilated first and to the greatest extent relative to proximal arterioles and FA. Fatigue had little effect on dilatation of distal arterioles whereas dilatation of proximal arterioles and FA was suppressed. Latency of onset for vasodilatation decreased as duty cycle increased and was unaffected by fatigue. Vasodilatation and blood flow increase in proportion to integrated tension, with an ascending locus of vasomotor control and prolongation of post-contraction vasodilatation. With muscle fatigue, the locus of flow control resides in distal arterioles; both ascending and post-contraction vasodilatations are attenuated despite normal vasomotor tone.

Electroencephalogram (EEG) and electromyogram (EMG) signals during motion control reflect the interaction between the cortex and muscle. Therefore, dynamic information regarding the cortical-muscle system is of significance for the evaluation of muscle fatigue. We treated the cortex and muscle as a whole system and then applied graph theory and symbolic transfer entropy to establish an effective cortical-muscle network in the beta band (12-30 Hz) and the gamma band (30-45 Hz). Ten healthy volunteers were recruited to participate in the isometric contraction at the level of 30% maximal voluntary contraction. Pre- and post-fatigue EEG and EMG data were recorded. According to the Borg scale, only data with an index greater than 14<19 were selected as fatigue data. The results show that after muscle fatigue: (1) the decrease in the force-generating capacity leads to an increase in STE of the cortical-muscle system; (2) increases of dynamic forces in fatigue leads to a shift from the beta band to gamma band in the activity of the cortical-muscle network; (3) the areas of the frontal and parietal lobes involved in muscle activation within the ipsilateral hemibrain have a compensatory role. Classification based on support vector machine algorithm showed that the accuracy is improved compared to the brain network. These results illustrate the regulation mechanism of the cortical-muscle system during the development of muscle fatigue, and reveal the great potential of the cortical-muscle network in analyzing motor tasks.

To estimate muscle oxygen uptake and quantify fatigue during exercise in ambulatory individuals with spinal muscular atrophy (SMA) and healthy controls.

Cardiovascular responses of traditional resistance (TS) training have been extensively explored. However, the fatigue mechanisms associated with an intra-set rest configuration (ISR) have not been investigated. This study compares two modalities of set configurations for resistance exercise that equates work to rest ratios and measures the central and peripheral fatigue in combination with cortical, hemodynamic and cardiovascular measures.

Alcohol consumption affects many organs and tissues, including skeletal muscle. However, the molecular mechanism of ethanol action on skeletal muscle remains unclear. Here, using molecular dynamics simulations and single channel recordings, we show that ethanol interacts with a negatively charged amino acid within an extracellular region of the neuromuscular nicotinic acetylcholine receptor (nAChR), thereby altering its global conformation and reducing the single channel current amplitude. Charge reversal of the negatively charged amino acid abolishes the nAChR-ethanol interaction. Moreover, using transgenic animals harboring the charge-reversal mutation, ex vivo measurements of muscle force production show that ethanol counters fatigue in wild type but not homozygous αE83K mutant animals. In accord, in vivo studies of motor coordination following ethanol administration reveal an approximately twofold improvement for wild type compared to homozygous mutant animals. Together, the converging results from molecular to animal studies suggest that ethanol counters muscle fatigue through its interaction with neuromuscular nAChRs.

Chemotherapy-induced fatigue is a multidimensional symptom. Oxidative stress has been proposed as a working mechanism for anthracycline-induced cardiotoxicity. In this study, doxorubicin (DOX) was tested on skeletal muscle function. Doxorubicin induced impaired ex vivo skeletal muscle relaxation followed in time by contraction impediment, which could be explained by DOX-induced changes in Ca(2+) responses of myotubes in vitro. The Ca(2+) responses in skeletal muscle, however, could not be explained by oxidative stress.

The development of fatigue elicits multiple adaptations from the neuromuscular system. Muscle synergies are common patterns of neuromuscular activation that have been proposed as the building blocks of human movement. We wanted to identify possible adaptations of muscle synergies to the development of fatigue in the upper limb. Recent studies have reported that synergy structure remains invariant during the development of fatigue, but these studies did not examine isolated synergies. We propose a novel approach to characterise synergy adaptations to fatigue by taking advantage of the spatial tuning of synergies. This approach allows improved identification of changes to individual synergies that might otherwise be confounded by changing contributions of overlapping synergies. To analyse upper limb synergies, we applied non-negative matrix factorization to 14 EMG signals from muscles of 11 participants performing isometric contractions. A preliminary multidirectional task was used to identify synergy directional tuning. A subsequent fatiguing task was designed to fatigue the participants in their synergies' preferred directions. Both tasks provided virtual reality feedback of the applied force direction and magnitude, and were performed at 40% of each participant's maximal voluntary force. Five epochs were analysed throughout the fatiguing task to identify progressive changes of EMG amplitude, median frequency, synergy structure, and activation coefficients. Three to four synergies were sufficient to account for the variability contained in the original data. Synergy structure was conserved with fatigue, but interestingly synergy activation coefficients decreased on average by 24.5% with fatigue development. EMG amplitude did not change systematically with fatigue, whereas EMG median frequency consistently decreased across all muscles. These results support the notion of a neuromuscular modular organisation as the building blocks of human movement, with adaptations to synergy recruitment occurring with fatigue. When synergy tuning properties are considered, the reduction of activation of muscle synergies may be a reliable marker to identify fatigue.

The objective detection of muscle fatigue reports the moment at which a muscle fails to sustain the required force. Such a detection prevents any further injury to the muscle following fatigue. However, the objective detection of muscle fatigue still requires further investigation. This paper presents an algorithm that employs a new fatigue index for the objective detection of muscle fatigue using a double-step binary classifier. The proposed algorithm involves analyzing the acquired sEMG signals in both the time and frequency domains in a double-step investigation. The first step involves calculating the value of the integrated EMG (IEMG) to determine the continuous contraction of the muscle being investigated. It was found that the IEMG value continued to increase with prolonged muscle contraction and progressive fatigue. The second step involves differentiating between the high-frequency components (HFC) and low-frequency components (LFC) of the EMG, and calculating the fatigue index. Basically, the segmented EMG signal was filtered by two band-pass filters separately to produce two sub-signals, namely, a high-frequency sub-signal (HFSS) and a low-frequency sub-signal (LFSS). Then, the instantaneous mean amplitude (IMA) was calculated for the two sub-signals. The proposed algorithm indicates that the IMA of the HFSS tends to decrease during muscle fatigue, while the IMA of the LFSS tends to increase. The fatigue index represents the difference between the IMA values of the LFSS and HFSS, respectively. Muscle fatigue was found to be present and was objectively detected when the value of the proposed fatigue index was equal to or greater than zero. The proposed algorithm was tested on 75 EMG signals that were extracted from 75 middle deltoid muscles. The results show that the proposed algorithm had an accuracy of 94.66% in distinguishing between conditions of muscle fatigue and non-fatigue.

Acylcarnitine metabolites have gained attention as biomarkers of nutrient stress, but their physiological relevance and metabolic purpose remain poorly understood. Short-chain carnitine conjugates, including acetylcarnitine, derive from their corresponding acyl-CoA precursors via the action of carnitine acetyltransferase (CrAT), a bidirectional mitochondrial matrix enzyme. We show here that contractile activity reverses acetylcarnitine flux in muscle, from net production and efflux at rest to net uptake and consumption during exercise. Disruption of this switch in mice with muscle-specific CrAT deficiency resulted in acetyl-CoA deficit, perturbed energy charge, and diminished exercise tolerance, whereas acetylcarnitine supplementation produced opposite outcomes in a CrAT-dependent manner. Likewise, in exercise-trained compared to untrained humans, post-exercise phosphocreatine recovery rates were positively associated with CrAT activity and coincided with dramatic shifts in muscle acetylcarnitine dynamics. These findings show acetylcarnitine serves as a critical acetyl buffer for working muscles and provide insight into potential therapeutic strategies for combatting exercise intolerance.

The flavanol (-)-epicatechin, a component of cacao (cocoa), has been shown to have multiple health benefits in humans. Using 1-year-old male mice, we examined the effects of 15 days of (-)-epicatechin treatment and regular exercise on: (1) exercise performance, (2) muscle fatigue, (3) capillarity, and (4) mitochondrial biogenesis in mouse hindlimb and heart muscles. Twenty-five male mice (C57BL/6N) were randomized into four groups: (1) water, (2) water-exercise (W-Ex), (3) (-)-epicatechin ((-)-Epi), and (4) (-)-epicatechin-exercise ((-)-Epi-Ex). Animals received 1 mg kg(-1) of (-)-epicatechin or water (vehicle) via oral gavage (twice daily). Exercise groups underwent 15 days of treadmill exercise. Significant increases in treadmill performance (∼50%) and enhanced in situ muscle fatigue resistance (∼30%) were observed with (-)-epicatechin. Components of oxidative phosphorylation complexes, mitofilin, porin, nNOS, p-nNOS, and Tfam as well as mitochondrial volume and cristae abundance were significantly higher with (-)-epicatechin treatment for hindlimb and cardiac muscles than exercise alone. In addition, there were significant increases in skeletal muscle capillarity. The combination of (-)-epicatechin and exercise resulted in further increases in oxidative phosphorylation-complex proteins, mitofilin, porin and capillarity than (-)-epicatechin alone. These findings indicate that (-)-epicatechin alone or in combination with exercise induces an integrated response that includes structural and metabolic changes in skeletal and cardiac muscles resulting in greater endurance capacity. These results, therefore, warrant the further evaluation of the underlying mechanism of action of (-)-epicatechin and its potential clinical application as an exercise mimetic.

Purpose: Rapid muscle fatigue limits clinical applications of functional electrical stimulation (FES) for individuals with motor impairments. This study aimed to characterize the sustainability of muscle force elicited with a novel transcutaneous nerve stimulation technique. Method: A hemiplegic chronic stroke survivor was recruited in this case study. Clustered subthreshold pulses of 60-μs with kilohertz (12.5 kHz) carrier frequency (high-frequency mode, HF) were delivered transcutaneously to the proximal segment of the median/ulnar nerve bundles to evaluate the finger flexor muscle fatigue on both sides of the stroke survivor. Conventional nerve stimulation technique with 600-μs pulses at 30 Hz (low-frequency mode, LF) served as the control condition. Fatigue was evoked by intermittently delivering 3-s stimulation trains with 1-s resting. For fair comparison, initial contraction forces (approximately 30% of the maximal voluntary contraction) were matched between the HF and LF modes. Muscle fatigue was evaluated through elicited finger flexion forces (amplitude and fluctuation) and muscle activation patterns quantified by high-density electromyography (EMG). Result: Compared with those from the LF stimuli, the elicited forces declined more slowly, and the force plateau was higher under the HF stimulation for both the affected and contralateral sides, resulting in a more sustainable force output at higher levels. Meanwhile, the force fluctuation under the HF stimulation increased more slowly, and, thus, was smaller after successive stimulation trains compared with the LF stimuli, indicating a less synchronized activation of muscle fibers. The efficiency of the muscle activation, measured as the force-EMG ratio, was also higher in the HF stimulation mode. Conclusion: Our results indicated that the HF nerve stimulation technique can reduce muscle fatigue in stroke survivors by maintaining a higher efficiency of muscle activations compared with the LF stimulation. The technique can help improve the performance of neurorehabilitation methods based on electrical stimulation, and facilitate the utility of FES in clinical populations.