Muscle Force Generation Research Articles

Inhibition of smooth muscle force generation by focal adhesion kinase inhibitors in the hyperplastic human prostate.

Smooth muscle contraction may be critical for lower urinary tract symptoms (LUTS) in patients with benign prostate hyperplasia and requires stable anchorage of the cytoskeleton to the cell membrane. These connections are regulated by focal adhesion kinase (FAK). Here, we addressed the involvement of FAK in the regulation of smooth muscle contraction in hyperplastic human prostate tissues. Prostate tissues were obtained from radical prostatectomy. Expression of FAK and focal adhesion proteins was assessed by Western blot analysis and immunohistochemical stainings. Effects of the FAK inhibitors PF-573228 and Y-11 on contraction of prostate strips were examined in the organ bath. Expression of FAK and focal adhesion proteins (integrin-5α, paxilin, and c-Src) was detected by Western blot analysis in prostate samples. By double immunofluorescence staining with calponin and pan-cytokeratin, expression of FAK was observed in stromal and epithelial cells. Immunoreactivity for FAK colocalized with integrin-5α, paxilin, talin, and c-Src. Stimulation of prostate tissues with the α1-adrenergic agonist phenylephrine increased the phosphorylation state of FAK at Tyr³⁹⁷ and Tyr⁹²⁵ with different kinetics, which was blocked by the α1-adrenoceptor antagonist tamsulosin. Norepinephrine and phenylephrine induced concentration-dependent contractions of prostate strips. Both FAK inhibitors PF-573228 and Y-11 significantly inhibited norepinephrine- and phenylephrine-induced contractions. Finally, PF-573228 and Y-11 inhibited contractions induced by electric field stimulation, which was significant at the highest frequency. In conclusion, α1-adrenergic smooth muscle contraction or its regulation involves FAK in the human prostate. Consequently, FAK may be involved in the pathophysiology of LUTS and in current or future LUTS therapies.

The effectiveness of FES-evoked EMG potentials to assess muscle force and fatigue in individuals with spinal cord injury.

The evoked electromyographic signal (eEMG) potential is the standard index used to monitor both electrical changes within the motor unit during muscular activity and the electrical patterns during evoked contraction. However, technical and physiological limitations often preclude the acquisition and analysis of the signal especially during functional electrical stimulation (FES)-evoked contractions. Hence, an accurate quantification of the relationship between the eEMG potential and FES-evoked muscle response remains elusive and continues to attract the attention of researchers due to its potential application in the fields of biomechanics, muscle physiology, and rehabilitation science. We conducted a systematic review to examine the effectiveness of eEMG potentials to assess muscle force and fatigue, particularly as a biofeedback descriptor of FES-evoked contractions in individuals with spinal cord injury. At the outset, 2867 citations were identified and, finally, fifty-nine trials met the inclusion criteria. Four hypotheses were proposed and evaluated to inform this review. The results showed that eEMG is effective at quantifying muscle force and fatigue during isometric contraction, but may not be effective during dynamic contractions including cycling and stepping. Positive correlation of up to r = 0.90 (p < 0.05) between the decline in the peak-to-peak amplitude of the eEMG and the decline in the force output during fatiguing isometric contractions has been reported. In the available prediction models, the performance index of the eEMG signal to estimate the generated muscle force ranged from 3.8% to 34% for 18 s to 70 s ahead of the actual muscle force generation. The strength and inherent limitations of the eEMG signal to assess muscle force and fatigue were evident from our findings with implications in clinical management of spinal cord injury (SCI) population.

Control of reach extent with the paretic and nonparetic arms after unilateral sensorimotor stroke II: planning and adjustments to control movement distance.

Nondisabled adults utilize both planning and feedback-based compensatory adjustments to control actual distance moved for skilled reach actions. The purpose of this study was to determine whether individuals post-stroke utilize planning and compensatory adjustments to control movement distance for reaches to targets that vary in distance. Individuals with mild to moderate motor impairment after stroke and nondisabled adults reached with both arms to targets presented at three distances (8, 16, 24 cm). The control of movement distance was compared between arms (control, nonparetic, and paretic) as to the use of planning (correlation of peak acceleration with movement distance), compensatory adjustments prior to peak velocity (correlation of time to peak velocity with movement distance), and compensatory adjustments after peak velocity (variance in movement distance accounted for by deterministic statistical model). The correlation of peak acceleration with movement distance for reaches with the paretic arm was significantly less than controls suggesting a decreased reliance on planning. Feedback-based compensatory adjustments, however, were present prior to and after peak velocity that assisted in achievement of movement distance in a similar manner as controls. Overall reach performance with the paretic arm was impaired, however, as evidenced by greater endpoint error and longer movement times than controls. The decreased use of planning to control movement distance after stroke suggests that the selected motor command was suboptimal in producing the desired movement outcome and may be related to an inability to generate muscle force quickly, lack of knowledge of arm dynamics due to decreased arm use, or lesion characteristics.

Utility of red blood cell acetylcholinesterase measurement in mechanically ventilated subjects after organophosphate poisoning.

Many patients with organophosphate poisoning require mechanical ventilation. Muscle acetylcholinesterase (AChE) activity determines the impairment of muscle force generation, and red blood cell (RBC) AChE has been regarded as a surrogate for muscle AChE in organophosphate poisoning. Therefore, this study was conducted to investigate whether RBC AChE at presentation can predict the duration of mechanical ventilatory support and whether RBC AChE at weaning can predict weaning trial outcomes in patients on mechanical ventilation for organophosphate poisoning. This retrospective observational case series identified 74 patients with a history of mechanical ventilation secondary to organophosphate poisoning and whose RBC AChE levels were available at presentation to the emergency department, at 24 h of presentation, or at weaning. Data were collected for plasma cholinesterase assay results, weaning outcome, duration of mechanical ventilation, and details of patient management (including ICU stay and amount of atropine and pralidoxime administered). RBC AChE activity levels at presentation and at 24 h of presentation had a negative correlation with duration of mechanical ventilation in subjects who ingested dimethyl organophosphate, but this correlation was not observed for those who had ingested diethyl or unclassified organophosphate. The optimal cutoff value of RBC AChE activity at presentation for predicting mechanical ventilation for < 7 d was 1,330 U/L in subjects intoxicated with dimethyl organophosphate. However, there was no difference in RBC AChE activity at the time of weaning trial between successful and failed weaning events, regardless of the chemical formulation of organophosphate. We conclude that RBC AChE activity within 24 h of presentation can help predict the duration of mechanical ventilation for dimethyl organophosphate intoxication; however, RBC AChE activity at the time of weaning trial may not be a suitable parameter for predicting a patient's ability to be weaned from mechanical ventilation.

Dystrophin involved in the susceptibility of slow muscles to hindlimb unloading via concomitant activation of TGF-β1/Smad3 signaling and ubiquitin-proteasome degradation in mice.

While it is well known that the slow-twitch muscles are vulnerable to microgravity conditions, the molecular and cellular mechanisms underlying this phenomenon remain unknown. Dystrophin, which constitutes an important link between the cytoskeleton and the extracellular matrix, is hypothesized to be involved in force generation and mechanical stabilization of the skeletal muscle. Here we have shown that after a 14-day hindlimb unloading (HU) of the C57BL/10 mice, the expression of dystrophin was significantly down-regulated in the fast-twitch myofibers, while in the slow-twitch myofibers, it was up-regulated. In order to investigate the role of dystrophin in HU-induced susceptibility to muscle atrophy, we compared the degradation signaling mechanisms of slow-twitch soleus muscle in dystrophin-deficient (mdx) and the wild-type (WT) mice. We found that mdx mice manifest less reduction of muscle mass and myofiber cross-sectional area than the control animals. Also, the expression of two ubiquitin ligases (MuRF1, Atrogin-1), which plays a crucial role in the ubiquitin-proteasome-mediated muscular degradation, was significantly down-regulated in soleus muscle of the hindlimb-unloaded mdx mice. In comparison, in the soleus muscle of unloaded WT mice, these ligases were significantly up-regulated. Whereas the hindlimb unloading reduced the expression of transforming growth factor β (TGF-β1)/Smad3 in mdx mice, in WT mice, the expression of this growth factor was augmented in response to unloading. Correspondingly, as a result of HU of the mdx mice, the expression of four subtypes of the myosin heavy chain and troponin I was reduced or it exhibited a delayed slow-to-fast transition. In summary, our results suggest that dystrophin exerts an intermediary and positive role in the disuse atrophy of the slow-twitch muscles. This effect is mediated through the activation of TGF-β1/Smad3 signaling and downstream ubiquitin-proteasome pathway.

Effects of Manganese (Mn) Administration on Muscle Force Generation during Hypoxia.

Effects of Manganese (Mn) Administration on Muscle Force Generation during Hypoxia.

Does use of a powered ankle-foot prosthesis restore whole-body angular momentum during walking at different speeds?

Whole-body angular momentum (H) influences fall risk, is tightly regulated during walking, and is primarily controlled by muscle force generation. People with transtibial amputations using passive-elastic prostheses typically have greater H compared with nonamputees. (1) Do people with unilateral transtibial amputations using passive-elastic prostheses have greater sagittal and frontal plane H ranges of motion during walking compared with nonamputees and compared with using powered prostheses? (2) Does use of powered ankle-foot prostheses result in equivalent H ranges in all planes of motion compared with nonamputees during walking as a result of normative prosthetic ankle power generation? Eight patients with a unilateral transtibial amputation and eight nonamputees walked 0.75, 1.00, 1.25, 1.50, and 1.75 m/s while we measured kinematics and ground reaction forces. We calculated H for participants using their passive-elastic prosthesis and a powered ankle-foot prosthesis and for nonamputees at each speed. Patients using passive-elastic prostheses had 32% to 59% greater sagittal H ranges during the affected leg stance phase compared with nonamputees at 1.00 to 1.75 m/s (p < 0.05). Patients using passive-elastic prostheses had 5% and 9% greater sagittal H ranges compared with using powered prostheses at 1.25 and 1.50 m/s, respectively (p < 0.05). Participants using passive-elastic prostheses had 29% and 17% greater frontal H ranges at 0.75 and 1.50 m/s, respectively, compared with nonamputees (p < 0.05). Surprisingly, patients using powered prostheses had 26% to 50% greater sagittal H ranges during the affected leg stance phase compared with nonamputees at 1.00 to 1.75 m/s (p < 0.05). Patients using powered prostheses also had 26% greater frontal H range compared with nonamputees at 0.75 m/s (p < 0.05). People with a transtibial amputation may more effectively regulate H at two specific walking speeds when using powered compared with passive-elastic prostheses. Our results support the hypothesis that an ankle-foot prosthesis capable of providing net positive work during the stance phase of walking reduces sagittal plane H; future studies are needed to validate our biomechanical findings with larger numbers of patients and should determine whether powered prostheses can decrease the risk of falls in patients with a transtibial amputation.

Effects of electrical nerve stimulation on force generation, oxygenation and blood volume in muscles of the immobilized human leg

Background. Transcutaneous electrical stimulation of the common peroneal nerve may be an additional clinical tool for enhancing venous return by active and passive mechanisms of muscle action in the immobilized leg. Purposes. To determine the effects of electrical stimulation of the common peroneal nerve to (1) produce force during isometric ankle joint dorsiflexion, and (2) alter muscle oxygenation and blood volume in the resting human leg. Methods. A novel electrical stimulator was applied to 28 legs of 14 healthy subjects. The force during isometric ankle joint dorsiflexion and myoelectric responses produced by stimulation-induced leg muscle contractions were investigated. Muscle oxygen saturation, blood volume and deoxygenated haemoglobin in the tibialis anterior and medial gastrocnemius muscles were measured by near-infrared spectroscopy during venous stasis (40 mmHg thigh tourniquet), with or without electrical stimulation. Results. The force produced during ankle joint dorsiflexion at the maximal stimulation intensity was 2.25 N (0.02–14.14) in the resting leg. Changes in muscle oxygen saturation during venous stasis, with or without electrical stimulation, were similar. Electrical stimulation during venous stasis caused 4–9% and 0.2–6% less increase in total muscle blood volume and deoxygenated hemoglobin compared to venous stasis alone. Conclusions. Nerve stimulation with a newly developed device partly counteracts increases in muscle blood volume and deoxygenated hemoglobin of the resting leg during venous stasis. Clinical relevance. The device stimulates active and passive mechanisms of leg muscle action that seems to enhance venous return in patients with impaired function.

Characterization of vascular endothelial and smooth muscle cell pathways and their contributions to myogenic and agonist‐mediated control (677.16)

Vascular smooth muscle cell contraction and relaxation is central to the local regulation of blood flow to tissue. At the arteriolar level, interactions between vascular endothelial cells and smooth muscel cells play critical role in determining the level of vascular tone. During mechanical and/or agonist stimulations, vascular Ca2+ dynamics are finely adjusted via a number of signaling pathways and the Ca2+ levels in the smooth muscle cells determine the level of contraction. To quantify how cellular Ca2+ dynamics are transformed into changes in vascular tone, we have constructed a cellular‐based model of isolated resistance vessel by integrating models of vessel wall mechanics, smooth muscle force generation, smooth muscle Ca2+ handling and electrophysiology with an endothelial electrophysiology and Ca2+ handling model. The dose‐response vasodilation and vasoconstriction data of different sizes of vessels in response to pharmacological vasoconstrictors and vasodilators, measured using a novel isovolumic myograph developed by Lu and Kassab are analyzed. The model simulates how changes in intraluminal pressure are used to maintain a constant vessel diameter during application of phenylephrine and acetylcholine. In order to simulate these sets of experimental data the model captures integrated vessel behavior including ionic (Ca2+, K+, Na+, etc.), IP3 and nitric oxide myoendothelial transport. Model analysis shows that α‐adrenergic pathways in smooth muscle and NO pathways in endothelium are sufficient to capture the experimentally observed phenylephrine and acetylcholine mediated responses.Grant Funding Source: NIH U01 HL118738, NSF CBET 1133260 and NIH P50‐GM094503

885 Targeting of smooth muscle force generation by inhibitors of focal adhesion kinase in the hyperplastic human prostate

885 Targeting of smooth muscle force generation by inhibitors of focal adhesion kinase in the hyperplastic human prostate

Sensorimotor function in preschool-aged children with expressive language disorder

The aim of the study was to evaluate functional motor performance and haptic object recognition in 5-year-old children with mild expressive language disorder (ELD) in comparison with age- and gender-matched healthy children. The subjects were classified by speech-language pathologist using The Reynell Developmental Language Scales III and Boehm Test of Basic Concepts: Preschool as children with mild ELD (n=29, incl. 23 boys and 6 girls) and children with typical language development as controls (n=29, incl. 23 boys and 6 girls). The children were examined for manual dexterity, ball skills, static and dynamic balance by Movement-ABC, haptic object recognition (HOR), hand-grip strength (HGS) and vertical jumping performance. Children with mild ELD demonstrated significantly higher scores (i.e., inferior performance) in all subtests of M-ABC (all p values <0.05), in haptic object recognition (p<0.01) and vertical jumping height (p<0.05) compared to controls. However, no statistically significant differences (p>0.05) emerged from HGS. Boys with mild ELD demonstrated higher results in impairment score (p<0.001), ball skills (p<0.01) and balance (p<0.01) of M-ABC, as well as in HOR (p<0.05). Girls with mild ELD showed higher impairment score (p<0.05) with lower percentile (p<0.05) in M-ABC, indicating inferior motor performance, and lower HGS for the non-dominant hand (p<0.05). Seven out of 29 (24.1%) children with mild ELD had definite or borderline motor difficulties, while only one child in control group (3.4%) demonstrated borderline motor difficulties. Children with mild expressive language disorder do not perform as well as controls in tests of functional motor skills, but their results in tests demanding maximal muscle force generation are in level with typically developing children. Boys and girls with mild ELD demonstrated higher impairment scores in M-ABC, indicating the need to follow their overall development more closely.

Muscle force depends on the amount of transversal muscle loading

Skeletal muscles are embedded in an environment of other muscles, connective tissue, and bones, which may transfer transversal forces to the muscle tissue, thereby compressing it. In a recent study we demonstrated that transversal loading of a muscle with 1.3Ncm−2 reduces maximum isometric force (Fim) and rate of force development by approximately 5% and 25%, respectively. The aim of the present study was to examine the influence of increasing transversal muscle loading on contraction dynamics.Therefore, we performed isometric experiments on rat M. gastrocnemius medialis (n=9) without and with five different transversal loads corresponding to increasing pressures of 1.3Ncm−2 to 5.3Ncm−2 at the contact area between muscle and load. Muscle loading was induced by a custom-made plunger which was able to move in transversal direction.Increasing transversal muscle loading resulted in an almost linear decrease in muscle force from 4.8±1.8% to 12.8±2% Fim. Compared to an unloaded isometric contraction, rate of force development decreased from 20.2±4.0% at 1.3Ncm−2 muscle loading to 34.6±5.7% at 5.3Ncm−2.Experimental observation of the impact of transversal muscle loading on contraction dynamics may help to better understand muscle tissue properties. Moreover, applying transversal loads to muscles opens a window to analyze three-dimensional muscle force generation. Data presented in this study may be important to develop and validate muscle models which enable simulation of muscle contractions under compression and enlighten the mechanisms behind.

Motor unit firing rate patterns during voluntary muscle force generation: a simulation study

Objective. Muscle force is generated by a combination of motor unit (MU) recruitment and changes in the discharge rate of active MUs. There have been two basic MU recruitment and firing rate paradigms reported in the literature, which describe the control of the MUs during force generation. The first (termed the reverse ‘onion skin’ profile), exhibits lower firing rates for lower threshold units, with higher firing rates occurring in higher threshold units. The second (termed the ‘onion skin’ profile), exhibits an inverse arrangement, with lower threshold units reaching higher firing rates. Approach. Using a simulation of the MU activity in a hand muscle, this study examined the force generation capacity and the variability of the muscle force magnitude at different excitation levels of the MU pool under these two different MU control paradigms. We sought to determine which rate/recruitment scheme was more efficient for force generation, and which scheme gave rise to the lowest force variability. Main results. We found that the force output of both firing patterns leads to graded force output at low excitation levels, and that the force generation capacity of the two different paradigms diverged around 50% excitation. In the reverse ‘onion skin’ pattern, at 100% excitation, the force output reached up to 88% of maximum force, whereas for the ‘onion skin’ pattern, the force output only reached up to 54% of maximum force at 100% excitation. The force variability was lower at the low to moderate force levels under the ‘onion skin’ paradigm than with the reverse ‘onion skin’ firing patterns, but this effect was reversed at high force levels. Significance. This study captures the influence of MU recruitment and firing rate organization on muscle force properties, and our results suggest that the different firing organizations can be beneficial at different levels of voluntary muscle force generation and perhaps for different tasks.

β-Hydroxy-β-methylbutyrate (HMB) prevents sepsis-induced diaphragm dysfunction in mice

Infections induce severe respiratory muscle weakness. Currently there are no treatments for this important clinical problem. We tested the hypothesis that β-hydroxy-β-methylbutyrate (HMB) would prevent sepsis-induced diaphragm weakness. Four groups of adult male mice were studied: controls (saline-injected), sepsis (intraperitoneal lipopolysaccharide), sepsis+HMB (injected intravenously), and HMB. Diaphragm force generation and indices of caspase 3, calpain, 20S proteasomal subunit, and double-stranded RNA-dependent protein kinase (PKR) activation were assessed after 24h. Sepsis elicited large reductions in diaphragm specific force generation at all stimulation frequencies. Endotoxin also activated caspase 3, calpain, the 20S proteasomal subunit and PKR in the diaphragm. HMB blocked sepsis-induced caspase 3, 20S proteasomal and PKR activation, but did not prevent calpain activation. Most importantly, HMB administration significantly attenuated sepsis-induced diaphragm weakness, preserving muscle force generation at all stimulation frequencies (p<0.01). We speculate that HMB may prove to be an important therapy in infected patients, with the potential to increase diaphragm strength, to reduce the duration of mechanical ventilation and to decrease mortality in this patient population.

EFFECT OF ENDURANCE EXERCISE ON SKELETAL MUSCLE WITH CHRONIC ALCOHOL INGESTION IN RAT

The effect of endurance exercise training on mechanical properties of skeletal muscle with chronic ethanol ingestion was determined in this study. Three to four-week-old male Wistar rats were randomly assigned to four groups: control (CON), control with exercise (CON/EXE), ethanol (ETH), and ethanol with exercise (ETH/EXE). The CON/EXE and ETH/EXE groups were trained to run for 12 weeks on a motor driven treadmill. ETH and ETH/EXE groups were adapted to a liquid alcohol diet (Lieber–DeCarli). Tetanic, twitch force generation, specific force, fatigue time, and shortening velocity of extensor digitorum longus (EDL) and soleus muscles were tested by using an in vitro muscle testing system. Our study shows that exercise does not improve the contractile properties of skeletal muscle with chronic ethanol ingestion indicated by similar twitch force and fatigue time between ETH/EXE and ETH groups in Types I and II fibers, and by lowered tetanic and specific forces in Type I fibers in ETH/EXE group compared to ETH group, possibly due to damage induced by oxidative stress. Future studies on interaction of the biochemical changes and contractile properties of the skeletal muscle with chronic ethanol ingestion will be conducted to better understand mechanisms behind alterations in contractile properties.

Surface EMG-force modelling for the biceps brachii and its experimental evaluation during isometric isotonic contractions

The aim of this study was to evaluate a surface electromyography (sEMG) signal and force model for the biceps brachii muscle during isotonic isometric contractions for an experimental set-up as well as for a simulation. The proposed model includes a new rate coding scheme and a new analytical formulation of the muscle force generation. The proposed rate coding scheme supposes varying minimum and peak firing frequencies according to motor unit (MU) type (I or II). Practically, the proposed analytical mechanogram allows us to tune the force contribution of each active MU according to its type and instantaneous firing rate. A subsequent sensitivity analysis using a Monte Carlo simulation allows deducing optimised input parameter ranges that guarantee a realistic behaviour of the proposed model according to two existing criteria and an additional one. In fact, this proposed new criterion evaluates the force generation efficiency according to neural intent. Experiments and simulations, at varying force levels and using the optimised parameter ranges, were performed to evaluate the proposed model. As a result, our study showed that the proposed sEMG–force modelling can emulate the biceps brachii behaviour during isotonic isometric contractions.

Individual Globular Domains and Domain Unfolding Visualized in Overstretched Titin Molecules with Atomic Force Microscopy

Titin is a giant elastomeric protein responsible for the generation of passive muscle force. Mechanical force unfolds titin’s globular domains, but the exact structure of the overstretched titin molecule is not known. Here we analyzed, by using high-resolution atomic force microscopy, the structure of titin molecules overstretched with receding meniscus. The axial contour of the molecules was interrupted by topographical gaps with a mean width of 27.7 nm that corresponds well to the length of an unfolded globular (immunoglobulin and fibronectin) domain. The wide gap-width distribution suggests, however, that additional mechanisms such as partial domain unfolding and the unfolding of neighboring domain multimers may also be present. In the folded regions we resolved globules with an average spacing of 5.9 nm, which is consistent with a titin chain composed globular domains with extended interdomain linker regions. Topographical analysis allowed us to allocate the most distal unfolded titin region to the kinase domain, suggesting that this domain systematically unfolds when the molecule is exposed to overstretching forces. The observations support the prediction that upon the action of stretching forces the N-terminal ß-sheet of the titin kinase unfolds, thus exposing the enzyme’s ATP-binding site and hence contributing to the molecule’s mechanosensory function.

Biophysical Analysis of the Putative Heart Failure Drug Omecamtiv Mecarbil

The small molecule omecamtiv mecarbil (OM), currently in late phase-2 clinical trials for treatment of heart failure, activates force generation by cardiac myosin. How OM increases force generation is not known. Crosslinking and molecular docking studies suggest that the compound binds to the relay/SH1/converter region of myosin, hypothesized to control the actin-activated pre to post power-stroke structural transition in the myosin catalytic and light-chain domains. These transitions drive force production by myosin. We are currently using time-resolved FRET and EPR distance measurements to detect the pre- and post-power-stroke structural states of myosin. We have performed these studies on tissue-purified β-cardiac and α-skeletal myosin, and on a recombinant cys-lite myosin II catalytic domain model from Dictyostelium discoideum. In each of the myosin isoforms, we find that OM binding increases the mole fraction of the myosin post power-stroke structural state in the presence of ATP analogs. Transient time-resolved FRET experiments, mixing FRET-labeled myosin with ATP, show that drug binding also alters the structural kinetics of the myosin recovery-stroke. Ongoing studies are investigating the affect of OM on the actin-activated power-stroke. These results show that OM has a direct effect on the power-stroke structural transition that drives force generation in muscle, thus providing structural insight into the mechanism of this new potential therapy for heart failure. Our results also highlight the utility of structure-based time-resolved FRET and EPR assays for the discovery and characterization of allosteric enzyme modulators.

Local Redox Modifications in Skeletal Muscle Differentially Affect Sarcoplasmic Reticulum Calcium Release and Muscle Force Generation

Aims: Reactive oxygen species are implicated in reducing muscle force production through oxidative cellular damage in skeletal muscle following repetitive fatiguing muscle contractions. We investigated whether shifting cellular redox status from an oxidized to reduced state could improve recovery of force production in skeletal muscle following fatigue. Methods: Mechanically-dissected intact single fibers from flexor digitorum brevis muscles of C57/BL6 mice were fatigued at physiological temperature (32 °C) with brief 150 ms duration 70 Hz tetani every 1 s for a total of 60 contractions. Fibers were superfused with the reducing agent dithiothretrol (DTT 1 mM, n = 10) for 20 min after fatigue-induced force loss was established. Results: The reducing agent, DTT, temporarily improved low-frequency (30 Hz) contractile force by 65% by increasing myofibrillar Ca2+ sensitivity without affecting sarcoplasmic reticulum (SR) Ca2+ release during recovery from fatigue. Intriguingly, addition of the oxidizing agent tert-butyl hydroperoxide (T-BOOH 10 μM, n=7) also temporarily improved 30 Hz force by 47% without affecting SR Ca2+ release. We then determined whether antioxidants and inhibitors of free radical production could prevent in the first place the oxidative damage associated with fatigue. We found that a mitochondria specific antioxidant (SS-31) and nitric oxide synthase inhibitor (L-NAME) recovered fatigue-induced impairments in SR Ca2+ release without affecting 30 Hz force. Conclusion: Antioxidants and inhibition of free radicals improves Ca2+ release during recovery, but has no effect on improving low-frequency force production. On the other hand, acute change in intracellular milieu using redox agents improves force development but does not affect Ca2+ release. Thus, proteins involved in SR Ca2+ release and myofibrillar contractile proteins show different dependency on the local redox micro-environment.

A musculoskeletal fatigue model for prediction of aviator neck manoeuvring loadings

A new musculoskeletal fatigue model was developed and demonstrated on the prediction of neck musculoskeletal loading and fatigue of fighter pilots during high-G aerial combat manoeuvring (ACM). A whole body articulated multi-body model with detailed neck musculature, representing a 50th percentile male, was utilised in this study. To account for the decrease of muscle force generation capacity during intensive muscle contraction, a new dynamic muscle fatigue model based on a fatigue-rest-recovery mechanism was incorporated to predict muscle fatigue responding to arbitrary neural excitations. Two flight postures, look-ahead and check-6, were investigated on their effects on neck loading during a 6-minute idealised ACM profile. The joint dynamics, muscle forces and fatigue levels, representing the neck biodynamic responses to the applied aircraft acceleration, were obtained and compared for these two postures. Significant differences are observed which show the check-6 posture poses much greater challenge to muscle force generation and induces quicker and severer muscle fatigue.