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ABSTRACT Introduction and Aims Methods Results Discussion Mitochondrial myopathies are rare genetic disorders for which no effective treatment exists. We previously showed that the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extends the lifespan of fast‐twitch skeletal muscle‐specific mitochondrial transcription factor A knockout (Tfam KO) mice, lacking the ability to transcribe mitochondrial DNA and displaying lethal mitochondrial myopathy. Our present aim was to assess whether the positive effect of CsA was associated with improved in vivo mitochondrial energy production.Mice were treated with CsA for 4 weeks, beginning at 12 weeks (i.e., before the terminal disease phase). Hindlimb plantar flexor muscles were fatigued by 80 contractions (40 Hz, 1.5 s on, 6 s off) while measuring force and energy metabolism using phosphorus‐31 magnetic resonance spectroscopy.Force decreased at similar rates in Tfam KO mice with and without the CsA treatment, reaching 50% of the baseline value after ~14 ± 1 contractions, which was faster than in control mice (25 ± 1 contractions). Phosphocreatine (PCr) decreased to ~10% of the control concentration in Tfam KO mice, independent of the treatment, which was larger than the ~20% observed in control mice. The time constant of PCr recovery was higher in untreated Tfam KO than that in control muscle (+100%) and similar in untreated and CsA‐treated Tfam KO mice.The results do not support improved mitochondrial energy production as a mechanism underlying the prolonged lifespan of Tfam KO mitochondrial myopathy mice treated with CsA. Thus, other mechanisms must be involved, such as the previously observed CsA‐mediated protection against excessive mitochondrial Ca2+ accumulation. [ABSTRACT FROM AUTHOR]

Background: Alpine skiing involves the conversion of potential energy into kinetic energy, with the "velocity barrier" (VB) at each moment corresponding to the maximal velocity at which the athlete can ski while staying within the boundaries of the gates and maintaining control. Nevertheless, this concept has never been proven by evidence. The aim of this study was to experimentally test the existence of the VB and clarify its relationship with skier's force production/application capacities. Methods: Fourteen skiers were equipped with ski‐mounted force plates and a positional device and ran a 2‐turn Giant Slalom section starting from eight different heights on the slope. Three conditions were selected for further analysis: minimal entrance velocity (vmin); entrance velocity allowing the better section time (VB); maximal entrance velocity (vmax). Entrance velocity, section time, mean force output, ratio of force application effectiveness, velocity normalized energy dissipation, and path length were compared between the three conditions. Moreover, skier's mechanical energy and velocity curves were compared all along the section between the three conditions using SPM analysis. Results: The section time was reduced in VB compared to vmin (p < 0.001) and vmax (p = 0.002). Skiers presented an incapacity to increase force output beyond the VB (p = 0.441) associated with a lower force application effectiveness (p = 0.005). Maximal entrance velocity was associated to higher energy dissipation (p < 0.001) and path length (p = 0.005). Conclusion: The present study experimentally supports the existence of the VB. The force production/application capacities seem to limit the skiing effectiveness beyond the VB, associated to increased energy dissipations and path length. [ABSTRACT FROM AUTHOR]

The aim of the present study was to compare the effect of chronic concentric or eccentric training on position sense and joint reaction angle, in healthy, untrained young men. Twenty-four men were randomly assigned into a pure concentric (CT) or a pure eccentric (ET) group and performed for 8 weeks, one training session/week, 75 maximal knee extensors contractions. Before and 48 h after the first (W1) and the last (W8) training sessions, knee joint position sense and joint reaction angle were assessed at three different knee angles (i.e. 30°, 45° and 60°). At the same time points, indirect indices of exercise-induced muscle damage (EIMD) were evaluated (i.e. range of motion [ROM], optimal angle, maximum isometric, concentric and eccentric torques, delayed onset muscle soreness [DOMS] and blood creatine kinase concentrations [CK]). Forty-eight hours post W1, position sense, reaction angle and all EIMD indices were significantly changed for both groups (p < 0.05; η2: 0.125–0.618), however, greater alterations were observed after ET. Significant correlations were found, in both groups, between the training-induced changes of position sense, reaction angles and the changes of EIMD biomarkers (r: −0.855–0.825; p < 0.005). No significant changes were found 48 h post W8 for position sense, reaction angle and EIMD indices (p > 0.285) for both CT or ET groups. In conclusion, exercise-induced changes in position sense and reaction angle, were related to the magnitude of EIMD, and not by the type of muscle contraction per se. Highlights Exercise induced changes in position sense and reaction angle, were related to the magnitude of EIMD, and not by the type of muscle contraction per se. After the 1st training session eccentric exercise caused greater disturbances, compared to concentric exercise, in EIMD indices which caused concomitant disturbances to position sense and knee reaction angle. 8 weeks of either eccentric or concentric training leads to preservation of position sense and knee reaction angle 48 h after maximal intensity exercise of either types of muscle contraction. [ABSTRACT FROM AUTHOR]

Key points: We used the idea of synergic control and the framework of the uncontrolled manifold hypothesis to explore the synergic control of a single muscle.Individual motor units in flexor digitorum superficialis formed two‐three groups (MU‐modes) with parallel changes in firing frequency, robust over force‐up and force‐down segments.There were strong force‐stabilizing synergies in the MU‐mode space during accurate cyclical force production.The results show, for the first time, that the idea of synergic control is applicable to individual muscles.The results suggest that segmental spinal mechanisms, such as recurrent inhibition and stretch reflex, probably play a major role in the synergic control of action. In the present study, for the first time, we have used the idea of synergic control and the framework of the uncontrolled manifold (UCM) hypothesis to test two hypotheses: (i) individual motor units are organized into stable groups (MU‐modes) with parallel scaling of firing rates with changes in the muscle force, and (ii) the gains of MU‐mode involvement co‐vary to stabilize the desired force magnitude. Young healthy subjects performed accurate cyclical force tracing tasks at 1 Hz by pressing with intermediate phalanges; only one finger was instructed to produce force at a time. Surface electromyographic signal from flexor digitorum superficialis was recorded and used to identify individual motor units and their firing frequencies. Principal component analysis with rotation and factor extraction was used to identify MU‐modes, which showed similar compositions over the force‐up and force‐down task segments. Inter‐cycle variance analysis in the MU‐mode space confirmed the existence of strong synergies stabilizing finger force. There were no synergies stabilizing MU‐mode magnitude in the space of individual motor units. This is the first application of the UCM framework to the neural control of a single muscle. It extends the applicability of this approach to analysis of individual muscles. We discuss the importance of the findings for the idea of hierarchical control and the notion of muscle compartments. The results suggest that segmental spinal mechanisms, such as recurrent inhibition and stretch reflex, probably play a major role in the synergic control of action. Key points: We used the idea of synergic control and the framework of the uncontrolled manifold hypothesis to explore the synergic control of a single muscle.Individual motor units in flexor digitorum superficialis formed two‐three groups (MU‐modes) with parallel changes in firing frequency, robust over force‐up and force‐down segments.There were strong force‐stabilizing synergies in the MU‐mode space during accurate cyclical force production.The results show, for the first time, that the idea of synergic control is applicable to individual muscles.The results suggest that segmental spinal mechanisms, such as recurrent inhibition and stretch reflex, probably play a major role in the synergic control of action. [ABSTRACT FROM AUTHOR]

Myosin binding protein-C slow (sMyBP-C) comprises a family of accessory proteins in skeletal muscles that bind both myosin and actin filaments. Herein, we examined the role of sMyBP-C in adult skeletal muscles using in vivo gene transfer and clustered regularly interspaced short palindromic repeats technology to knock down all known sMyBP-C variants. Our findings, confirmed in two different skeletal muscles, demonstrated efficient knockdown (KD) of sMyBP-C (>70%) resulting in notably decreased levels of thick, but not thin, filament proteins ranging from ~50% for slow and fast myosin to ~20% for myomesin. Consistent with this, A bands were selectively distorted, and sarcomere length was significantly reduced. Contrary to earlier in vitro studies showing that addition of recombinant sMyBP-C slows down the formation of actomyosin crossbridges, our work demonstrates that KD of sMyBP-C in intact myofibers results in decreased contraction and relaxation kinetics under no-load conditions. Similarly, KD muscles develop markedly reduced twitch and tetanic force and contraction velocity. Taken together, our results show that sMyBP-C is essential for the regular organization and maintenance of myosin filaments into A bands and that its structural role precedes its ability to regulate actomyosin crossbridges. [ABSTRACT FROM AUTHOR]

Skeletal muscle fibers are giant multinucleated cells wherein individual nuclei govern the protein synthesis in a finite volume of cytoplasm; this is termed the myonuclear domain (MND). The factors that controlMNDsize remain to be defined. In the present study, we studied the contribution of the NAD+-dependent deacetylase, sirtuin 1 (SIRT1), to the regulation of nuclear number and MND size. For this, we isolated myofibers from mice with tissue-specific inactivation (mKO) or inducible over-expression (imOX) of SIRT1 and analyzed the 3D organisation of myonuclei. In imOX mice, the number of nuclei was increased whilst the average MND size was decreased as compared to littermate controls. Our findings were the opposite in mKO mice. Muscle stem cell (satellite cell) numbers were reduced in mKO muscles, a possible explanation for the lower density of myonuclei in these mice; however, no change was observed in imOX mice, suggesting that other factors might also be involved, such as the functional regulation of stem cells/muscle precursors. Interestingly, however, the changes in the MND volume did not impact the force-generating capacity of muscle fibers. Taken together, our results demonstrate that SIRT1 is a key regulator of MND sizes, although the underlying molecular mechanisms and the cause-effect relationship between MND and muscle function remain to be fully defined. [ABSTRACT FROM AUTHOR]

Keywords: contractile kinetics; excitation-contraction coupling; force production; muscle contraction EN contractile kinetics excitation-contraction coupling force production muscle contraction 1579 1580 2 04/04/22 20220401 NES 220401 Excitation-contraction coupling (ECC) describes the physiological process by which an electrical stimulus is converted to a mechanical response. I Drosophila i larval and mature adult muscle is striated and can be categorized into three main types: (i) tubular muscles (which include most adult skeletal muscles); (ii) indirect flight muscles; and (iii) supercontractile muscles (which are found in the viscera, including the heart and larval body wall muscles) (Peron I et al i . 2009). A comparison of vertebrate muscle- and fibre-type-specific contractile kinetics to those reported in this study would be beneficial in determining which vertebrate muscle shares the highest degree of similarity with and would benefit most from future muscular contraction research from the I Drosophila i model. [Extracted from the article]

Control of intracellular transport is poorly understood, and functional ramifications of tubulin isoform differences between cell types are mostly unexplored. Motors' force production and detachment kinetics are critical for their group function, but how microtubule (MT) details affect these properties - if at all - is unknown. We investigated these questions using both a vesicular transport human kinesin, kinesin-1, and also a mitotic kinesin likely optimized for group function, kinesin-5, moving along either bovine brain or MCF7(breast cancer) MTs. We found that kinesin-1 functioned similarly on the two sets of MTs - in particular, its mean force production was approximately the same, though due to its previously reported decreased processivity, the mean duration of kinesin-1 force production was slightly decreased on MCF7 MTs. In contrast, kinesin-5's function changed dramatically on MCF7 MTs: its average detachment force was reduced and its force-velocity curve was different. In spite of the reduced detachment force, the force-velocity alteration surprisingly improved high-load group function for kinesin-5 on the cancer-cell MTs, potentially contributing to functions such as spindle-mediated chromosome separation. Significant differences were previously reported for C-terminal tubulin tails in MCF7 versus bovine brain tubulin. Consistent with this difference being functionally important, elimination of the tails made transport along the two sets of MTs similar. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a central role in skeletal muscle metabolism. We used skeletalmuscle-specific AMPKα1α2 double-knockout (mdKO) mice to provide direct genetic evidence of the physiological importance of AMPK in regulatingmuscle exercise capacity, mitochondrial function, and contraction-stimulated glucose uptake. Exercise performance was significantly reduced in the mdKO mice, with a reduction in maximal force production and fatigue resistance. An increase in the proportion of myofibers with centralized nuclei was noted, as well as an elevated expression of interleukin 6 (IL-6) mRNA, possibly consistent with mild skeletal muscle injury. Notably, we found thatAMPKα1 and AMPKα2 isoforms are dispensable for contraction-induced skeletal muscle glucose transport, except for male soleus muscle. However, the lack of skeletal muscle AMPK diminished maximal ADP-stimulated mitochondrial respiration, showing an impairment at complex I. This effect was not accompanied by changes in mitochondrial number, indicating that AMPK regulates muscle metabolic adaptation through the regulation of musclemitochondrial oxidative capacity and mitochondrial substrate utilization but not baseline mitochondrial muscle content. Together, these results demonstrate that skeletal muscle AMPK has an unexpected role in the regulation of mitochondrial oxidative phosphorylation that contributes to the energy demands of the exercising muscle. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine whether split step (small hop before step) would be more beneficial than no-split condition in simulated tennis response situation. In addition, it was studied if movement time of the response is related to separately measured force production capabilities and reflex sensitivity of the players. Nine skilled male tennis players participated in this study. Subjects stood on a force plate and reacted to a light signal and moved to appointed direction as fast as possible. With split step the participants were 13.1% faster (P <0.05) than without split step from the start to the distal end of the so called close range movement continuum (2.70 m). This was mainly explained by 43.6% faster time (P <0.05) from the signal to the onset of force production. Greater vertical forces were observed with split step: 15.7% greater F(z) mean force (P <0.05), 60.0% greater F(z) peak force (P<0.01). In split step both mean (r= − 0.813, P <0.01) and peak (r=−0.765, P <0.05) vertical forces (Fz) correlated negatively with the time from the onset of the force production to the photocell. With split step higher EMGs were observed in muscles responsible for ankle joint movement indicating that different strategies were used. Due to the split step the players were able to start the movement faster which mostly explains the advantages over the no-split step condition. Split step condition may also benefit from stretch shortening type of muscle action. [ABSTRACT FROM AUTHOR]

Introduction: The dystrophic features in hindlimb skeletal muscles of female mdx mice are unclear. Methods: We analyzed force-generating capacity and force decline after lengthening contraction-induced damage (fragility). Results: Young (6-month-old) female mdx mice displayed reduced force-generating capacity (−18%) and higher fragility (23% force decline) compared with female age-matched wild-type mice. These 2 dystrophic features were less accentuated in young female than in young male mdx mice (−32% and 42% force drop). With advancing age, force-generating capacity decreased and fragility increased in old (20 month) female mdx mice (−21% and 57% force decline), but they were unchanged in old male mdx mice. Moreover, estradiol treatment had no effect in old female mdx mice. Conclusions: Female gender-related factors mitigate dystrophic features in young but not old mdx mice. Further studies are warranted to identify the beneficial gender-related factor in dystrophic muscle. Muscle Nerve, 2013 [ABSTRACT FROM AUTHOR]

Background Heavy prenatal alcohol exposure can result in diverse and extensive damage to the central nervous system, including the cerebellum, basal ganglia, and cerebral cortex. Given that these brain regions are involved in the generation and maintenance of motor force, we predicted that prenatal alcohol exposure would adversely affect this parameter of motor control. We previously reported that children with gestational alcohol exposure experience significant deficits in regulating isometric (i.e., constant) force. The purpose of this study was to determine whether these children exhibit similar deficits when producing isotonic (i.e., graded) force. Methods Children with heavy prenatal alcohol exposure and typically developing children completed a series of isotonic force contractions by exerting force on a load cell to match a criterion target force displayed on a computer monitor. Two levels of target force (5 or 20% of maximum voluntary force) were investigated in combination with varying levels of visual feedback. Results Compared with control children, children with heavy prenatal alcohol exposure generated isotonic force signals that were less accurate, more variable, and less complex in the time domain. Specifically, interactions were found between group and visual feedback for response accuracy and signal complexity, suggesting that these children have greater difficulty altering their motor output when visual feedback is low. Conclusions These data suggest that prenatal alcohol exposure produces deficits in regulating isotonic force, which presumably result from alcohol-related damage to developing brain regions involved in motor control. These children will most likely experience difficulty performing basic motor skills and daily functional skills that require coordination of finely graded force. Therapeutic strategies designed to increase feedback and, consequently, facilitate visual-motor integration could improve isotonic force production in these children. [ABSTRACT FROM AUTHOR]

Aim: We analysed the effect of physiological doses of androgens following orchidectomy on skeletal muscle and bone of male rats, as well as the relationships between muscle performance, hypertrophy and the Akt/mammalian target of rapamycin (mTOR) signalling pathway involved in the control of anabolic and catabolic muscle metabolism. Methods: We studied the soleus muscle and tibia from intact rats (SHAM), orchidectomized rats treated for 3 months with vehicle (ORX), nandrolone decanoate (NAN) or dihydrotestosterone (DHT). Results: Orchidectomy had very little effect on the soleus muscle. However, maximal force production by soleus muscle (+69%) and fatigue resistance (+35%) in NAN rats were both increased when compared with ORX rats. In contrast, DHT treatment did not improve muscle function. The relative number of muscle fibres expressing slow myosin heavy chain and citrate synthase activity were not different in NAN and ORX rats. Moreover, NAN and DHT treatments did not modify muscle weights and cross-sectional area of muscle fibres. Furthermore, phosphorylation levels of downstream targets of the Akt/mTOR signalling pathway, Akt, ribosomal protein S6 and eukaryotic initiation factor 4E-binding protein 1 were similar in muscles of NAN, DHT and ORX rats. In addition, trabecular tibia from NAN and DHT rats displayed higher bone mineral density and bone volume when compared with ORX rats. Only in NAN rats was this associated with increased bone resistance to fracture. Conclusion: Physiological doses of androgens are beneficial to muscle performance in orchidectomized rats without relationship to muscle and fibre hypertrophy and activation of the Akt/mTOR signalling pathway. Taken together our data clearly indicate that the activity of androgens on muscle and bone could participate in the global improvement of musculoskeletal status in the context of androgen deprivation induced by ageing. [ABSTRACT FROM AUTHOR]

Abstract Action monitoring has been studied in many tasks by means of measuring the error-related negativity (Ne/ERN), but never in a motor control task requiring precise force production. Errors in discrete choice reaction tasks are the result of incorrect selections, but errors in force production can also arise from incorrect executions. ERPs were obtained while participants produced low or high isometric forces with their left or right hand. As expected, incorrect choices of hand elicited an Ne/ERN. Interestingly, Ne/ERNs were also present in the less discrete selection error of an incorrect choice of force, but only when erroneously a low instead of a high force was chosen. In both force ranges, no Ne/ERNs were found after errors in execution. These errors showed a large positivity in feedback ERPs and, similar to correct responses, a prolonged negativity in response ERPs. We propose that, compared to selection errors, the time uncertainty aspects of execution errors and the resulting changing response representations prohibit error detection by the internal monitoring system responsible for generating the Ne/ERN. [ABSTRACT FROM AUTHOR]