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Contractile function of skeletal muscle relies on the ability of muscle fibers to trigger and propagate action potentials (APs). These electrical signals are created by transmembrane ion transport through ion channels and membrane transporter systems. In this regard, the Cl- ion channel 1 (ClC-1) and the Na+/K--ATPase (NKA) are central for maintaining ion homeostasis across the sarcolemma during intense contractile activity. Therefore, this randomized controlled trial aimed to investigate the changes in ClC-1 and specific NKA subunit isoform expression in response to six weeks (18 training sessions) of high-load resistance exercise (HLRE) and low-load blood flow restricted resistance exercise (BFRRE), respectively. HLRE was conducted as 4 sets of 12 repetitions of knee extensions performed at 70% of 1 repetition maximum (RM), while BFRRE was conducted as 4 sets of knee extensions at 30% of 1RM performed to volitional fatigue. Furthermore, the potential associations between protein expression and contractile performance were investigated. We show that muscle ClC-1 abundance was not affected by either exercise modality, whereas NKA subunit isoforms [Formula: see text]2 and [Formula: see text]1 increased equally by appx. 80-90% with BFRRE (p < 0.05) and 70-80% with HLRE (p < 0.05). No differential impact between exercise modalities was observed. At baseline, ClC-1 protein expression correlated inversely with dynamic knee extensor strength (r=-0.365, p = 0.04), whereas no correlation was observed between NKA subunit content and contractile performance at baseline. However, training-induced changes in NKA [Formula: see text]2 subunit (r = 0.603, p < 0.01) and [Formula: see text]1 subunit (r = 0.453, p < 0.05) correlated with exercise-induced changes in maximal voluntary contraction. These results suggest that the initial adaptation to resistance-based exercise does not involve changes in ClC-1 abundance in untrained skeletal muscle, and that increased content of NKA subunits may facilitate increases in maximal force production.

Background: Low-load resistance exercise (LL-RE) with blood flow restriction (BFR) promotes increased metabolic response and fatigue, as well as more pronounced myoelectric activity than traditional LL-RE. Some studies have shown that the relative pressure applied during exercise may have an effect on these variables, but existing evidence is contradictory. Purpose: The aim of this study was to systematically review and pool the available evidence on the differences in neuromuscular and metabolic responses at LL-RE with different pressure of BFR. Methods: The systematic review and meta-analysis was reported according to PRISMA items. Searches were performed in the following databases: CINAHL, PubMed, Scopus, SPORTDiscus and Web of Science, until June 15, 2021. Randomized or non-randomized experimental studies that analyzed LL-RE, associated with at least two relative BFR pressures [arterial occlusion pressure (AOP)%], on myoelectric activity, fatigue, or metabolic responses were included. Random-effects meta-analyses were performed for MVC torque (fatigue measure) and myoelectric activity. The quality of evidence was assessed using the PEDro scale. Results: Ten studies were included, all of moderate to high methodological quality. For MVC torque, there were no differences in the comparisons between exercise with 40-50% vs. 80-90% AOP. When analyzing the meta-analysis data, the results indicated differences in comparisons in exercise with 15-20% 1 repetition maximum (1RM), with higher restriction pressure evoking greater MVC torque decline (4 interventions, 73 participants; MD = -5.05 Nm [95%CI = -8.09; -2.01], p = 0.001, I 2 = 0%). For myoelectric activity, meta-analyses indicated a difference between exercise with 40% vs. 60% AOP (3 interventions, 38 participants; SMD = 0.47 [95%CI = 0.02; 0.93], p = 0.04, I2 = 0%), with higher pressure of restriction causing greater myoelectric activity. This result was not identified in the comparisons between 40% vs. 80% AOP. In analysis of studies that adopted pre-defined repetition schemes, differences were found (4 interventions, 52 participants; SMD = 0.58 [95%CI = 0.11; 1.05], p = 0.02, I 2 = 27%). Conclusion: The BFR pressure applied during the LL-RE may affect the magnitude of muscle fatigue and excitability when loads between 15 and 20% of 1RM and predefined repetition protocols (not failure) are prescribed, respectively. Systematic Review Registration: [http://www.crd.york.ac.uk/prospero], identifier [CRD42021229345].

This study compared elbow flexor (EF; experiment 1) and knee extensor (KE; experiment 2) maximal compound action potential (Mmax) amplitude between long-term resistance trained (LTRT; n = 15 and n = 14, 6 ± 3 and 4 ± 1 yr of training) and untrained (UT; n = 14 and n = 49) men, and examined the effect of normalizing electromyography (EMG) during maximal voluntary torque (MVT) production to Mmax amplitude on differences between LTRT and UT. EMG was recorded from multiple sites and muscles of EF and KE, Mmax was evoked with percutaneous nerve stimulation, and muscle size was assessed with ultrasonography (thickness, EF) and magnetic resonance imaging (cross-sectional area, KE). Muscle-electrode distance (MED) was measured to account for the effect of adipose tissue on EMG and Mmax. LTRT displayed greater MVT (+66%-71%, P < 0.001), muscle size (+54%-56%, P < 0.001), and Mmax amplitudes (+29%-60%, P ≤ 0.010) even when corrected for MED (P ≤ 0.045). Mmax was associated with the size of both muscle groups (r ≥ 0.466, P ≤ 0.011). Compared with UT, LTRT had higher absolute voluntary EMG amplitude for the KE (P < 0.001), but not the EF (P = 0.195), and these differences/similarities were maintained after correction for MED; however, Mmax normalization resulted in no differences between LTRT and UT for any muscle and/or muscle group (P ≥ 0.652). The positive association between Mmax and muscle size, and no differences when accounting for peripheral electrophysiological properties (EMG/Mmax), indicates the greater absolute voluntary EMG amplitude of LTRT might be confounded by muscle morphology, rather than providing a discrete measure of central neural activity. This study therefore suggests limited agonist neural adaptation after LTRT.NEW & NOTEWORTHY In a large sample of long-term resistance-trained individuals, we showed greater maximal M-wave amplitude of the elbow flexors and knee extensors compared with untrained individuals, which appears to be at least partially mediated by differences in muscle size. The lack of group differences in voluntary EMG amplitude when normalized to maximal M-wave suggests that differences in muscle morphology might impair interpretation of voluntary EMG as an index of central neural activity.

In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), altered membrane excitability often occurs in exercising muscles demonstrating muscle dysfunction regardless of any psychiatric disorder. Increased oxidative stress is also present in many ME/CFS patients and could affect the membrane excitability of resting muscles.
Seventy-two patients were examined at rest, during an incremental cycling exercise and during a 10-min post-exercise recovery period. All patients had at least four criteria leading to a diagnosis of ME/CFS. To explore muscle membrane excitability, M-waves were recorded during exercise (rectus femoris (RF) muscle) and at rest (flexor digitorum longus (FDL) muscle). Two plasma markers of oxidative stress (thiobarbituric acid reactive substance (TBARS) and oxidation-reduction potential (ORP)) were measured. Plasma potassium (K+) concentration was also measured at rest and at the end of exercise to explore K+ outflow.
Thirty-nine patients had marked M-wave alterations in both the RF and FDL muscles during and after exercise while the resting values of plasma TBARS and ORP were increased and exercise-induced K+ outflow was decreased. In contrast, 33 other patients with a diagnosis of ME/CFS had no M-wave alterations and had lower baseline levels of TBARS and ORP. M-wave changes were inversely proportional to TBARS and ORP levels.
Resting muscles of ME/CFS patients have altered muscle membrane excitability. However, our data reveal heterogeneity in some major biomarkers in ME/CFS patients. Measurement of ORP may help to improve the diagnosis of ME/CFS. Trial registration Ethics Committee \"Ouest II\" of Angers (May 17, 2019) RCB ID: number 2019-A00611-56.

The antiarrhythmic sodium-channel blocker mexiletine is used to treat patients with myotonia. However, around 30% of patients do not benefit from mexiletine due to poor tolerability or suboptimal response. Safinamide is an add-on therapy to levodopa for Parkinson\'s disease. In addition to MAOB inhibition, safinamide inhibits neuronal sodium channels, conferring anticonvulsant activity in models of epilepsy. Here, we investigated the effects of safinamide on skeletal muscle hNav1.4 sodium channels and in models of myotonia, in-vitro and in-vivo. Using patch-clamp, we showed that safinamide reversibly inhibited sodium currents in HEK293T cells transfected with hNav1.4. At the holding potential (hp) of -120 mV, the half-maximum inhibitory concentrations (IC50) were 160 and 33 μM at stimulation frequencies of 0.1 and 10 Hz, respectively. The calculated affinity constants of safinamide were dependent on channel state: 420 μM for closed channels and 9 μM for fast-inactivated channels. The p.F1586C mutation in hNav1.4 greatly impaired safinamide inhibition, suggesting that the drug binds to the local anesthetic receptor site in the channel pore. In a condition mimicking myotonia, i.e. hp. of -90 mV and 50-Hz stimulation, safinamide inhibited INa with an IC50 of 6 μM, being two-fold more potent than mexiletine. Using the two-intracellular microelectrodes current-clamp method, action potential firing was recorded in vitro in rat skeletal muscle fibers in presence of the chloride channel blocker, 9-anthracene carboxylic acid (9-AC), to increase excitability. Safinamide counteracted muscle fiber hyperexcitability with an IC50 of 13 μM. In vivo, oral safinamide was tested in the rat model of myotonia. In this model, intraperitoneal injection of 9-AC greatly increased the time of righting reflex (TRR) due to development of muscle stiffness. Safinamide counteracted 9-AC induced TRR increase with an ED50 of 1.2 mg/kg, which is 7 times lower than that previously determined for mexiletine. In conclusion, safinamide is a potent voltage and frequency dependent blocker of skeletal muscle sodium channels. Accordingly, the drug was able to counteract abnormal muscle hyperexcitability induced by 9-AC, both in vitro and in vivo. Thus, this study suggests that safinamide may have potential in treating myotonia and warrants further preclinical and human studies to fully evaluate this possibility.

Hypokalaemic periodic paralysis (HypoPP) is caused by mutations of Cav1.1, and Nav1.4 which result in an aberrant gating pore current. Hyperkalaemic periodic paralysis (HyperPP) is due to a gain-of-function mutation of the main alpha pore of Nav1.4. This study used muscle velocity recovery cycles (MVRCs) to investigate changes in interictal muscle membrane properties in vivo.
MVRCs and responses to trains of stimuli were recorded in tibialis anterior and compared in patients with HyperPP(n = 7), HypoPP (n = 10), and normal controls (n = 26).
Muscle relative refractory period was increased, and early supernormality reduced in HypoPP, consistent with depolarisation of the interictal resting membrane potential. In HyperPP the mean supernormality and residual supernormality to multiple conditioning stimuli were increased, consistent with increased inward sodium current and delayed repolarisation, predisposing to spontaneous myotonic discharges.
The in vivo findings suggest the interictal resting membrane potential is depolarized in HypoPP, and mostly normal in HyperPP. The MVRC findings in HyperPP are consistent with presence of a window current, previously proposed on the basis of in vitro expression studies. Although clinically similar, HyperPP was electrophysiologically distinct from paramyotonia congenita.
MVRCs provide important in vivo data that complements expression studies of ion channel mutations.

It has been recurrently observed that, for compound muscle action potentials (M wave) recorded over the innervation zone of the vastus lateralis, the descending portion of the first phase generally shows an \"inflection\" or \"shoulder.\" We sought to clarify the electrical origin of this shoulder-like feature and examine its implications. M waves evoked by maximal single shocks to the femoral nerve were recorded in monopolar and bipolar configurations from 126 individuals using classical (10-mm recording diameter, 20-mm inter-electrode distance) electrodes and from eight individuals using small electrodes arranged in a linear array. The changes of the M-wave waveform at different positions along the muscle fibers\' direction were examined. The shoulder was identified more frequently in monopolar (97%) than in bipolar (46%) M waves. The shoulder of M waves recorded at different distances from the innervation zone had the same latency. Furthermore, the shoulder of the M wave recorded over the innervation zone coincided in latency with the positive peak of that recorded beyond the muscle. The positive phase of the M wave detected 20 mm away from the innervation zone was essentially composed of non-propagating components. The shoulder-like feature in monopolar and bipolar M waves results from the termination of action potentials at the superficial aponeurosis of the vastus lateralis. We conclude that, only the amplitude of the first phase, and not the second, of M waves recorded monopolarly and/or bipolarly in close proximity to the innervation zone can be used reliably to monitor possible changes in muscle membrane excitability.

The periodic paralyses are a group of skeletal muscle channelopathies characterizeed by intermittent attacks of muscle weakness often associated with altered serum potassium levels. The underlying genetic defects include mutations in genes encoding the skeletal muscle calcium channel Cav1.1, sodium channel Nav1.4, and potassium channels Kir2.1, Kir3.4, and possibly Kir2.6. Our increasing knowledge of how mutant channels affect muscle excitability has resulted in better understanding of many clinical phenomena which have been known for decades and sheds light on some of the factors that trigger attacks. Insights into the pathophysiology are also leading to new therapeutic approaches.

This study was designed to examine separately the changes in the first and second phases of the muscle compound action potential (M-wave) during and after a sustained 3-minutes maximal voluntary contraction (MVC). M-waves were evoked by supramaximal single shocks to the femoral nerve given at 10-seconds intervals throughout a sustained isometric 3-minutes MVC and also during six brief MVCs performed throughout a 30-minutes recovery period. The amplitude, duration, and area of the M-wave first and second phases, together with muscle conduction velocity and force, were measured. During the 3-minutes MVC, the amplitude of the first phase increased progressively for the first minute (33%-43%, P<.01) and remained stable thereafter, whereas the second phase initially increased for 25-35 seconds (30%-50%, P<.01), but subsequently decreased significantly before stabilizing. During the recovery period, the amplitude of the M-wave first phase showed a decreasing trend, returning to pre-fatigue values (P>.01) within 5-10 minutes, while the second phase increased progressively and remained higher than control (7%-20%, P<.01) after the 30-minutes recovery time. Maximal cross-correlations between the time course of the first phase amplitude and those of conduction velocity and force (0.9-0.93) occurred for a lag of 0 seconds, whereas maximal cross-correlations corresponding to the second-phase amplitude (0.6-0.7) occurred for a 50-seconds time lag. The present findings indicate that the potentiation of the first phase results from impaired muscle membrane excitability. The peak-to-peak amplitude and second-phase amplitude are not valid indicators of muscle excitability as they might be critically affected by muscle architectural features.