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

Uncertainties and implications of applying aggregated data for spatial modelling of atmospheric ammonia emissions

Ammonia emissions vary greatly at a local scale, and effects (eutrophication, acidification) occur primarily close to sources. Therefore it is important that spatially distributed emission estimates are located as accurately as possible. The main source of ammonia emissions is agriculture, and therefore agricultural survey statistics are the most important input data to an ammonia emission inventory alongside per activity estimates of emission potential. In the UK, agricultural statistics are collected at farm level, but are aggregated to parish level, NUTS-3 level or regular grid resolution for distribution to users. In this study, the Modifiable Areal Unit Problem (MAUP), associated with such amalgamation, is investigated in the context of assessing the spatial distribution of ammonia sources for emission inventories. England was used as a test area to study the effects of the MAUP. Agricultural survey data at farm level (point data) were obtained under license and amalgamated to different areal units or zones: regular 1-km, 5-km, 10-km grids and parish level, before they were imported into the emission model. The results of using the survey data at different levels of amalgamation were assessed to estimate the effects of the MAUP on the spatial inventory. The analysis showed that the size and shape of aggregation zones applied to the farm-level agricultural statistics strongly affect the location of the emissions estimated by the model. If the zones are too small, this may result in false emission “hot spots”, i.e., artificially high emission values that are in reality not confined to the zone to which they are allocated. Conversely, if the zones are too large, detail may be lost and emissions smoothed out, which may give a false impression of the spatial patterns and magnitude of emissions in those zones. The results of the study indicate that the MAUP has a significant effect on the location and local magnitude of emissions in spatial inventories where amalgamated, zonal data are used

Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca²⁺ Handling.

The contractile function of skeletal muscle declines during intense or prolonged physical exercise, that is, fatigue develops. Skeletal muscle fibers fatigue acutely during highly intense exercise when they have to rely on anaerobic metabolism. Early stages of fatigue involve impaired myofibrillar function, whereas decreased Ca <sup>2+</sup> release from the sarcoplasmic reticulum (SR) becomes more important in later stages. SR Ca <sup>2+</sup> release can also become reduced with more prolonged, lower intensity exercise, and it is then related to glycogen depletion. Increased reactive oxygen/nitrogen species can cause long-lasting impairments in SR Ca <sup>2+</sup> release resulting in a prolonged force depression after exercise. In this article, we discuss molecular and cellular mechanisms of the above fatigue-induced changes, with special focus on multiple mechanisms to decrease SR Ca <sup>2+</sup> release to avoid energy depletion and preserve muscle fiber integrity. We also discuss fatigue-related effects of exercise-induced Ca <sup>2+</sup> fluxes over the sarcolemma and between the cytoplasm and mitochondria

The meaning of life

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Modulation of torque evoked by wide-pulse, high-frequency neuromuscular electrical stimulation and the potential implications for rehabilitation and training.

The effectiveness of neuromuscular electrical stimulation (NMES) for rehabilitation is proportional to the evoked torque. The progressive increase in torque (extra torque) that may develop in response to low intensity wide-pulse high-frequency (WPHF) NMES holds great promise for rehabilitation as it overcomes the main limitation of NMES, namely discomfort. WPHF NMES extra torque is thought to result from reflexively recruited motor units at the spinal level. However, whether WPHF NMES evoked force can be modulated is unknown. Therefore, we examined the effect of two interventions known to change the state of spinal circuitry in opposite ways on evoked torque and motor unit recruitment by WPHF NMES. The interventions were high-frequency transcutaneous electrical nerve stimulation (TENS) and anodal transcutaneous spinal direct current stimulation (tsDCS). We show that TENS performed before a bout of WPHF NMES results in lower evoked torque (median change in torque time-integral: - 56%) indicating that WPHF NMES-evoked torque might be modulated. In contrast, the anodal tsDCS protocol used had no effect on any measured parameter. Our results demonstrate that WPHF NMES extra torque can be modulated and although the TENS intervention blunted extra torque production, the finding that central contribution to WPHF NMES-evoked torques can be modulated opens new avenues for designing interventions to enhance WPHF NMES

Toxic doses of caffeine are needed to increase skeletal muscle contractility.

Discrepant results have been reported regarding an intramuscular mechanism underlying the ergogenic effect of caffeine on neuromuscular function in humans. Here, we reevaluated the effect of caffeine on muscular force production in humans and combined this with measurements of the caffeine dose-response relationship on force and cytosolic free [Ca <sup>2+</sup> ] ([Ca <sup>2+</sup> ] <sub>i</sub> ) in isolated mouse muscle fibers. Twenty-one healthy and physically active men (29 ± 9 yr, 178 ± 6 cm, 73 ± 10 kg, mean ± SD) took part in the present study. Nine participants were involved in two experimental sessions during which supramaximal single and paired electrical stimulations (at 10 and 100 Hz) were applied to the femoral nerve to record evoked forces. Evoked forces were recorded before and 1 h after ingestion of 1) 6 mg caffeine/kg body mass or 2) placebo. Caffeine plasma concentration was measured in 12 participants. In addition, submaximal tetanic force and [Ca <sup>2+</sup> ] <sub>i</sub> were measured in single mouse flexor digitorum brevis (FDB) muscle fibers exposed to 100 nM up to 5 mM caffeine. Six milligrams of caffeine per kilogram body mass (plasma concentration ~40 µM) did not increase electrically evoked forces in humans. In superfused FDB single fibers, millimolar caffeine concentrations (i.e., 15- to 35-fold above usual concentrations observed in humans) were required to increase tetanic force and [Ca <sup>2+</sup> ] <sub>i</sub> . Our results suggest that toxic doses of caffeine are required to increase muscle contractility, questioning the purported intramuscular ergogenic effect of caffeine in humans

Ammonia emission and deposition in Scotland and its potential environmental impacts

The main source of atmospheric ammonia (NH3) in Scotland is livestock agriculture, which accounts for 85% of emissions. The local magnitude of emissions therefore depends on livestock density, type, and management, with major differences occurring in various parts of Scotland. Local differences in agricultural activities therefore result in a wide range of NH3 emissions, ranging from less than 0.2 kg N ha(-1) year(-1) in remote areas of the Scottish Highlands to over 100 kg N ha(-1) year-1 in areas with intensive poultry farming. Scotland can be divided loosely into upland and lowland areas, with NH3 emission being less than and more than 5 kg N ha(-1) year(-1), respectively. Many semi-natural ecosystems in Scotland are vulnerable to nitrogen deposition, including bogs, moorlands, and the woodland ground flora. Because NH3 emissions occur in the rural environment, the local deposition to sensitive ecosystems may be large, making it essential to assess the spatial distribution of NH3 emissions and deposition. A spatial model is applied here to map NH3 emissions and these estimates are applied in atmospheric dispersion and deposition models to estimate atmospheric concentrations of NH3 and NH4+, dry deposition of NH3, and wet deposition of NHx. Although there is a high level of local variability, modelled NH3 concentrations show good agreement with the National Ammonia Monitoring Network, while wet deposition is largest at high altitude sites in the south and west of Scotland. Comparison of the modelled NHx deposition fields with estimated thresholds for environmental effects ("critical loads") shows that thresholds are exceeded across most of lowland Scotland and the Southern Uplands. Only in the cleanest parts of the north and west is nitrogen deposition not a cause for concern. Given that the most intense effects occur within a few kilometres of sources, it is suggested that local spatial abatement policies would be a useful complement to traditional policies that mitigate environmental effects based on emission reduction technologies

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

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) Ca(2+) 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 Ca(2+) leak at rest, and depressed force production due to impaired SR Ca(2+) 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 Ca(2+)-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