Rate Of Force Generation Research Articles

Threshold variations of medial pterygoid single motor units during vertical or horizontal force tasks.

To test the hypotheses that (a) the force thresholds at onset of medial pterygoid muscle single motor unit (SMU) activity do not decrease with an increase in the rate of force generation in standardised vertical or horizontal jaw-force tasks, and (b) there is evidence for functional heterogeneity within the medial pterygoid muscle. In 14healthy participants, electromyographic recordings of the right medial pterygoid muscle were performed with intramuscular fine-wire electrodes during four isometric force tasks: vertical, horizontal contralateral, horizontal protrusion and horizontal ipsilateral, performed at two rates of force development (slow ramp, fast ramp). Computer tomography scans confirmed electrode location within the muscle, which was divided into medial and lateral parts. Force thresholds of onset of discriminated SMUs were compared between rates in each task; significance accepted at p<0.05. Of 45 SMU force thresholds studied in one or more tasks, there was no significant difference between slow and fast ramp within each force task, except slow ramp thresholds from the lateral part during the vertical force task were significantly higher than fast ramp thresholds. Reversals of recruitment order between tasks provided evidence for functional heterogeneity within the muscle. Force thresholds of the vertical tasks (range: 1-292.6N) were mostly higher than for the horizontal tasks (range: 0.1-12.5N). The data are consistent with the proposal that the medial pterygoid muscle stabilises the jaw in the vertical plane during isometric force generation in the jaw closing, as well as horizontal directions.

The Role of Hip Abductor Strength in Identifying Older Persons at Risk of Falls: A Diagnostic Accuracy Study.

Background/ObjectivesEarly detection of fall risk in persons older than 65 is of clinical relevance, but the diagnostic accuracy of currently used functional tests (eg short physical performance battery [SPPB] and timed up and go test [TUG]) to assess older persons’ fall risks remains moderate. Recent literature highlights the importance of strong hip abductors to prevent falls. We thus aimed to assess the diagnostic accuracy of hip abductor strength measures to assess older persons’ fall risks.MethodsHip abductor maximum voluntary isometric strength (ABD MVIS), rate of force generation (ABD RFG), and the SPPB and TUG functional fall risk assessments were assessed in 60 persons aged over 65 years (82.0 ± 6.1 years). The diagnostic accuracy (area under the curve [AUC], sensitivity [sens], specificity [spec], positive predictive value [PPV], negative predictive value [NPV], and positive and negative likelihood ratios [LR+, LR−]) was evaluated at a clinically important 90% sensitivity level. Cut-off values for clinical use were calculated.ResultsIn our population, hip ABD MVIS (AUC 0.8, sens 90.6%, spec 57.1%, PPV 70.7%, NPV 84.2%, LR+ 2.1, LR- 0.2, and cut-off value ≤ 1.1 N/kg) and hip ABD RFG (AUC 0.8, sens 90.6%, spec 46.4%, PPV 65.9%, NPV 81.3%, LR+ 1.7, LR- 0.2, and cut-off ≤ 8.47 N/kg/s) show diagnostic accuracy comparable to other fall risk assessments (SPPB and TUG) and a high net sensitivity when used in a test battery.ConclusionHip ABD MVIS or RFG shows good diagnostic accuracy to differentiate between older fallers and nonfallers compared to the chosen external criterion history of falls. The high net sensitivity when hip ABD MVIS or RFG is combined with currently used fall risk assessments shows promise in contributing value to a test battery and should be investigated further in longitudinal studies.

Bilateral Arm Training vs Unilateral Arm Training for Severely Affected Patients With Stroke: Exploratory Single-Blinded Randomized Controlled Trial

ObjectiveTo compare the effects of unilateral and bilateral arm training on arm impairment in severely affected patients with stroke. DesignSingle-blinded, randomized controlled trial. SettingInpatient rehabilitation center. ParticipantsFirst-time subacute patients (N=69) with stroke and a nonfunctional hand. Patients were stratified according to lesion location post hoc. InterventionsRepetitive bilateral arm training on an arm cycle followed by synchronized bilateral repetitive distal hand training or an identical unilateral arm training performed by the paretic limb only. Both unilateral and bilateral trainings were administered twice daily over 6 weeks. Main Outcome MeasuresThe primary outcome measure was the Fugl-Meyer Assessment (FMA) score for the arm, and secondary measures were biomechanical parameters measuring isometric force and rate of force generation. Outcome measures were assessed before, at the end of, and 2 weeks after intervention. ResultsPatients were homogeneous at study onset. All patients improved regarding the FMA arm score and most biomechanical parameters after intervention. Yet the post hoc analysis stratifying patients according to lesion location showed that patients with pure subcortical stroke, but not patients with cortical involvement of stroke, showed a significantly greater improvement (P=.022) following the bilateral training in FMA arm score (from 6.8±5.7 to 17.8±15.8) compared with unilateral training (from 6.5±7.8 to 8.7±8.6). ConclusionsThe benefit of bilateral arm training followed by repetitive bilateral hand training for motor control of the severely paretic upper limb may depend on lesion location. Further studies with larger sample size are required for the validation of these results.

The relative strength of common synaptic input to motor neurons is not a determinant of the maximal rate of force development in humans.

Correlation between motor unit discharge times, often referred to as motor unit synchronization, is determined by common synaptic input to motor neurons. Although it has been largely speculated that synchronization should influence the rate of force development, the association between the degree of motor unit synchronization and rapid force generation has not been determined. In this study, we examined this association with both simulations and experimental motor unit recordings. The analysis of experimental motor unit discharges from the tibialis anterior muscle of 20 healthy individuals during rapid isometric contractions revealed that the average motor unit discharge rate was associated with the rate of force development. Moreover, the extent of motor unit synchronization was entirely determined by the average motor unit discharge rate (R > 0.7, P < 0.0001). The simulation model demonstrated that the relative proportion of common synaptic input received by motor neurons, which determines motor unit synchronization, does not influence the rate of force development (R = 0.03, P > 0.05). Nonetheless, the estimates of correlation between motor unit spike trains were significantly correlated with the rate of force generation (R > 0.8, P < 0.0001). These results indicate that the average motor unit discharge rate, but not the degree of motor unit synchronization, contributes to most of the variance of human contractile speed among individuals. In addition, estimates of correlation between motor unit discharge times depend strongly on the number of identified motor units and therefore are not indicative of the strength of common input. NEW & NOTEWORTHY It is commonly assumed that motor unit synchronization has an impact on the rate of force development of a muscle. Here we present computer simulations and experimental data of human tibialis anterior motor units during rapid contractions that show that motor unit synchronization is not a determinant of the rate of force production. This conclusion clarifies the neural determinants of rapid force generation.

Intra-rater reliability of hip abductor isometric strength testing in a standing position in older fallers and non-fallers

BackgroundReduced hip muscle strength has been shown to be a major factor related to falls in older persons. However, comprehensive assessment of hip abduction strength in the clinical setting is challenging. The aim of this study was to investigate the feasibility and intra-rater reliability of a quick and simple hip abductor strength test in a functional standing position.MethodsIndividuals over 65 years of age were recruited from the geriatric department of a university hospital and an outpatient clinic. Thirty-two older subjects, including 16 fallers (≥1 fall during the last 12 months) and 16 non-fallers were included. Maximum voluntary isometric strength (MVIS) and rate of force generation (RFG) of the hip abductors of the right leg were evaluated in a standing position using a hand-held dynamometer. Two test-sessions were carried out. All hip strength values were normalized to participants’ weight. Reliability was determined using the intra-class correlation coefficient agreement (ICCagreement), the standard error of measurement (SEM) and a Bland and Altman analysis (BA).ResultsAll participants completed the strength tests, which took a mean 2.47 ± 0.49 min (one limb). Intra-rater reliability was higher for MVIS (0.98[0.95–0.99]) than RFG (ICC = 0.93[0.87–0.97]) for the entire sample. In the non-fallers, ICC was 0.98[0.95–1.00] (SEM = 0.08 N.kg− 1) for MVIS and 0.88[0.75–0.96] for RFG (SEM = 1.34 N.kg-1.s-1). In the fallers, ICC was 0.94[0.89–0.98] (SEM = 0.11 N.kg− 1) for MVIS and 0.93[0.84–0.98] (SEM = 1.12 N.kg− 1.s− 1) for RFG. The BA plot showed that the MVIS and RFG values did not differ across test-sessions, showing that no learning effect occurred (no systematic effect). The mean differences between test-sessions were larger and the LOA smaller in the fallers than in the non-fallers.ConclusionAssessment of hip strength in a standing position is feasible, rapid and reliable. We therefore recommend this position for clinical practice. Future studies should investigate the diagnostic value of hip abductor strength in standing to discriminate between fallers and non-fallers, and to determine if change in strength following a falls prevention program reduces the risk of falls.

The diagnostic accuracy of hip abductor strength in the fall risk of older persons

Persons aged over 65 years have an increased risk of falling and falls often trigger serious consequences like independency loss and increased mortality. An early detection of persons at risk of falling and a well-targeted fall prevention is thus of great interest. Previous studies showed that hip abductor strength is the muscle groups among all hip muscles, which is particularly related to the fall risk of older persons. Therefore we aimed to investigate the diagnostic accuracy of hip abductor strength by using history of falls as the external criterion. Hip abductor maximum voluntary isometric strength (ABD MVIS) and rate of force generation (ABD RFG) were assessed with a dynamometer fixed to a custom made frame in 60 persons aged over 65 years. The diagnostic accuracy [sensitivity (sens), specificity (spec), positive predictive value (PPV), negative predictive value (NPV), positive and negative likelihood ratios (LR + , LR − )] was assessed at a clinically important 90% sensitivity level. Cutoff values were calculated. Hip ABD MVIS (Sens. 90.6%, Spec. 57.1%, PPV 70.7%, NPV 84.2%, LR+ 2.11, LR− 0.16, cutoff value ≤ 1.06 N/kg) shows a slightly higher diagnostic accuracy than hip ABD RFG (Sens. 90.6%, Spec. 46.4%, PPV 65.9%, NPV 81.3%, LR+ 1.69, LR− 0.20, cutoff ≤ 8.47 N/kg/s). The results indicate that hip abductor strength shows a comparable diagnostic accuracy as other fall risk or mobility assessment tools (e.g. timed up and go test and short physical performance battery). Hip abductor strength shows a good diagnostic accuracy to discriminate between older fallers and non-fallers and therefore might be an interesting parameter for fall risk prediction and a targeted intervention program. This very promising parameter should further be investigated in prospective studies.

Intra-rater reliability of hip abductor isometric strength assessment in older fallers and non-fallers

Impaired muscle function at the hip has been implicated to be a major factor related to falls in older patients. Falls mostly occur in an upright position, therefore, the measurement of hip abductor strength in the often used side-lying or supine position is not functional. The aim was to investigate, for older persons at risk of falls, the feasibility and intra-rater reliability of a hip abductor test in standing position. To be included older persons had to be over 65 years. Fifteen fallers and 15 non-fallers participated in this study. Hip abductor strength was quantified with a hand-held dynamometer in standing position. Three trials were realized for both sessions. The raw force signals were exported and a low-pass filter was applied to attenuate high-frequency noise. The voluntary isometric strength (MVIS) was defined as the peak value reached within 0 to 4 s. The rate of force generation (RFG) was evaluated over 50 ms after 10% of the MVIS was reached. All variables were normalized for participants’ weight. Reliability was determined using intra-class correlation coefficient (ICCagreement), standard error measurement (SEM) and Bland and Altman plot analysis (mean differences between sessions and limit of agreement-LOA95%). The ICC above 0.75 indicated good reliability, those between 0.5 and 0.75 moderate reliability and those under 0.5, poor reliability. All recruited persons completed the strength test in standing position. The intra-rater reliability for MVIS parameter was good in non-fallers group (ICC = 0.94, SEM = 7.86 N) and fallers group (ICC = 0.91, SEM = 6.36 N). The RFG parameter was characterized with a moderate reliability in non-fallers group (ICC = 0.63, SEM = 114.24 N/s) and good reliability in fallers group (ICC = 0.83, SEM = 71.12 N/s). Bland and Altman analysis revealed small mean differences between sessions for MVIS (fallers: 1.41 N [LOA95%: −15.56;18.38] vs. non-fallers: 1.97 N [LOA95%: −21.26;25.20]) and larger mean differences for RFG (fallers: 44.28 N/s [LOA95%: −137.56;226.12] vs. non-fallers: −72.1 N/s [LOA95%: −428.60;284.10]). This standing approach is feasible to measure the hip abductors strength in older persons at risk of falls. Hip abductor strength assessment using a hand-held dynamometer provided consistent results when measured several times. For clinicians, this reliable test is easy to perform in daily use and interesting for testing the hip abductors strengths in a functional position.

Muscle hypertrophy in prediabetic men after 16 wk of resistance training

Resistance training of healthy young men typically results in muscle hypertrophy and a shift in vastus lateralis composition away from type IIx fibers to an increase in IIa fiber content. Our previous studies of 8 wk of resistance training found that many metabolic syndrome men and women paradoxically increased IIx fibers with a decrease in IIa fibers. To confirm the hypothesis that obese subjects might have muscle remodeling after resistance training very different from healthy lean subjects, we subjected a group of nine obese male volunteers to progressive resistance training for a total of 16 wk. In these studies, weight loss was discouraged so that muscle changes would be attributed to the training alone. Detailed assessments included comparisons of histological examinations of needle biopsies of vastus lateralis muscle pretraining and at 8 and 16 wk. Prolonging the training from 8 to 16 wk resulted in increased strength, improved body composition, and more muscle fiber hypertrophy, but euglycemic clamp-quantified insulin responsiveness did not improve. Similar to prior studies, muscle fiber composition shifted toward more fast-twitch type IIx fibers (23 to 42%). Eight weeks of resistance training increased the muscle expression of phosphorylated Akt2 and mTOR. Muscle GLUT4 expression increased, although insulin receptor and IRS-1 expression did not change. We conclude that resistance training of prediabetic obese subjects is effective at changing muscle, resulting in fiber hypertrophy and increased type IIx fiber content, and these changes continue up to 16 wk of training.NEW & NOTEWORTHY Obese, insulin-resistant men responded to 16 wk of progressive resistance training with muscle hypertrophy and increased strength and a shift in muscle fiber composition toward fast-twitch, type IIx fibers. Activation of muscle mTOR was increased by 8 wk but did not increase further at 16 wk despite continued augmentation of peak power and rate of force generation.

Evaluation of hip abductor and adductor strength in the elderly: a reliability study

BackgroundIn elderly individuals an increased muscle strength contributes to the diminution of the falls risk and associated adverse events. An increasing interest in lateral control exists due to the fatal consequences of postero-lateral falls. Therefore a proper assessment of frontal plane hip muscle strength in elderly is important but remains challenging.Therefore we aimed to investigate the feasibility and repeatability of a hip abductor and adductor maximum voluntary isometric strength (MVIS) and rate of force generation (RFG) test in elderly. This represents an initial step in the development process of a new and clinically relevant test that could lead to more specific treatment protocols for this population.MethodsIn this measurement focused study hip abduction (ABD) and adduction (ADD) MVIS and RFG were tested twice within one to three hours with a dynamometer fixed to a custom made frame in a geriatric population including fallers and non-fallers. Intraclass correlation coefficient (ICCagreement), standard error of measurement (SEM), and smallest detectable difference (SDD) were determined.ResultsAll recruited persons (N = 76; mean age (SD) 80.46 (7.05) years old) completed the tests. The average time needed to complete the strength tests was 10.58 min. (1.56) per muscle group. The reliability of the hip ABD and ADD was high with ICC’sagreement ranging from 0.83 to 0.97. The SDD varied between 18.1 and 81.8% depending on the muscle group and type of strength that was evaluated.ConclusionHip abductor and adductor strength measures in older person are feasible and reliable. However, the significance of moderate changes in these measurements may be limited by the large SDD and SEM. Therefore, physical therapist should be careful when using this measure for assessing the progress of an individual person in a daily clinical use.

A New and Improved View of Force Production

A central question in muscle contraction is “How is the energy release in ATP hydrolysis converted into mechanical force and work?” With the elucidation of the actomyosin ATPase reaction in the 1970s (1,2) and the fact that a large amount of free energy is produced during Pi release from an actomyosin-ADP-Pi species (3), the Pi release step from actomyosin-ADP-Pi must be associated with the generation of force and shortening. It was also known that increases in the [Pi] concentration in isometrically contracting skinned muscle fibers reduced isometric force (4).

Heart Failure: From Protein to Phenotype37MicroRNA-494 reduces ATF3 expression and promotes heart failure in cardiac hypertrophic remodeling in vivo38A novel recessive plakophilin-2 gene mutation causes severe arrhythmogenic dilated cardiomyopathy and sudden cardiac death at young age39Investigation of titin expression in explanted hearts with familial dilated cardiomyopathy and TTN truncating variants

Heart Failure: From Protein to Phenotype37MicroRNA-494 reduces ATF3 expression and promotes heart failure in cardiac hypertrophic remodeling in vivo38A novel recessive plakophilin-2 gene mutation causes severe arrhythmogenic dilated cardiomyopathy and sudden cardiac death at young age39Investigation of titin expression in explanted hearts with familial dilated cardiomyopathy and TTN truncating variants

Acute Strength Training Increases Responses to Stimulation of Corticospinal Axons

Acute strength training of forearm muscles increases resting twitch forces from motor cortex stimulation. It is unclear if such effects are spinal in origin and if they also occur with training of larger muscles. With the use of subcortical stimulation of corticospinal axons, the current study examined if one session of strength training of the elbow flexor muscles leads to spinal cord changes and if the type of training is important. In experiment 1, 10 subjects completed ballistic isometric training, ballistic concentric training, and no training (control) on separate days. In experiment 2, 13 subjects completed ballistic isometric training and slow-ramp isometric training. Before and after training, transcranial magnetic stimulation over the contralateral motor cortex elicited motor-evoked potentials (MEPs) in the resting biceps brachii, and electrical stimulation of corticospinal tract axons at the cervicomedullary junction elicited cervicomedullary motor-evoked potentials (CMEPs). Motor-evoked potential and CMEP twitch forces were also measured. In experiment 1, CMEPs and CMEP twitch forces were significantly facilitated after ballistic isometric training compared to control. In experiment 2, MEPs, MEP twitch forces, CMEPs, and CMEP twitch forces increased for 15 to 25 min after ballistic and slow-ramp isometric training. Via processes within the spinal cord, one session of strength training of the elbow flexors increases net output from motoneurons projecting to the trained muscles. Likely mechanisms include increased efficacy of corticospinal-motoneuronal synapses or increased motoneuron excitability. However, the rate of force generation during training is not important for inducing these changes. A concomitant increase in motor cortical excitability is likely. These short-term changes may represent initial neural adaptations to strength training.

Temperature-induced cardiac remodelling in fish.

ABSTRACTThermal acclimation causes the heart of some fish species to undergo significant remodelling. This includes changes in electrical activity, energy utilization and structural properties at the gross and molecular level of organization. The purpose of this Review is to summarize the current state of knowledge of temperature-induced structural remodelling in the fish ventricle across different levels of biological organization, and to examine how such changes result in the modification of the functional properties of the heart. The structural remodelling response is thought to be responsible for changes in cardiac stiffness, the Ca2+ sensitivity of force generation and the rate of force generation by the heart. Such changes to both active and passive properties help to compensate for the loss of cardiac function caused by a decrease in physiological temperature. Hence, temperature-induced cardiac remodelling is common in fish that remain active following seasonal decreases in temperature. This Review is organized around the ventricular phases of the cardiac cycle – specifically diastolic filling, isovolumic pressure generation and ejection – so that the consequences of remodelling can be fully described. We also compare the thermal acclimation-associated modifications of the fish ventricle with those seen in the mammalian ventricle in response to cardiac pathologies and exercise. Finally, we consider how the plasticity of the fish heart may be relevant to survival in a climate change context, where seasonal temperature changes could become more extreme and variable.

Molecular effects of the myosin activator omecamtiv mecarbil on contractile properties of skinned myocardium lacking cardiac myosin binding protein-C

Decreased expression of cardiac myosin binding protein-C (cMyBP-C) in the myocardium is thought to be a contributing factor to hypertrophic cardiomyopathy in humans, and the initial molecular defect is likely abnormal cross-bridge (XB) function which leads to impaired force generation, decreased contractile performance, and hypertrophy in vivo. The myosin activator omecamtiv mecarbil (OM) is a pharmacological drug that specifically targets the myosin XB and recent evidence suggests that OM induces a significant decrease in the in vivo motility velocity and an increase in the XB duty cycle. Thus, the molecular effects of OM maybe beneficial in improving contractile function in skinned myocardium lacking cMyBP-C because absence of cMyBP-C in the sarcomere accelerates XB kinetics and enhances XB turnover rate, which presumably reduces contractile efficiency. Therefore, parameters of XB function were measured in skinned myocardium lacking cMyBP-C prior to and following OM incubation. We measured ktr, the rate of force redevelopment as an index of XB transition from both the weakly- to strongly-bound state and from the strongly- to weakly-bound states and performed stretch activation experiments to measure the rates of XB detachment (krel) and XB recruitment (kdf) in detergent-skinned ventricular preparations isolated from hearts of wild-type (WT) and cMyBP-C knockout (KO) mice. Samples from donor human hearts were also used to assess the effects of OM in cardiac muscle expressing a slow β-myosin heavy chain (β-MHC). Incubation of skinned myocardium with OM produced large enhancements in steady-state force generation which were most pronounced at low levels of [Ca2+] activations, suggesting that OM cooperatively recruits additional XB’s into force generating states. Despite a large increase in steady-state force generation following OM incubation, parallel accelerations in XB kinetics as measured by ktr were not observed, and there was a significant OM-induced decrease in krel which was more pronounced in the KO skinned myocardium compared to WT skinned myocardium (58% in WT vs. 76% in KO at pCa 6.1), such that baseline differences in krel between KO and WT skinned myocardium were no longer apparent following OM-incubation. A significant decrease in the kdf was also observed following OM incubation in all groups, which may be related to the increase in the number of cooperatively recruited XB’s at low Ca2+-activations which slows the overall rate of force generation. Our results indicate that OM may be a useful pharmacological approach to normalize hypercontractile XB kinetics in myocardium with decreased cMyBP-C expression due to its molecular effects on XB behavior.

Energy cost and kinematics of level, uphill and downhill running: fatigue-induced changes after a mountain ultramarathon

This study aimed to determine whether the fatigue induced by a mountain ultramarathon (MUM) led to changes in energy cost and kinematic during level and graded running. Pre- and post-race, 14 ultratrail runners ran on a level, uphill (5%) and downhill (5%) treadmill at 10 km · h−1. Kinematic data were acquired using a photocell system. Post-race, the downhill energy cost increased by 13.1% (P < 0.001). No change was noted in level and uphill running. Duty factor and stride frequency were increased, whereas swing time, cycle time and stride length were decreased in all conditions (P < 0.05). Contact time was increased and the rate of force generation was decreased only in the uphill and downhill conditions (P < 0.05). Positive correlations were observed between performance time and the pre- to post-changes in the energy cost of level (r = 0.52, P = 0.04) and uphill running (r = 0.50, P = 0.04). MUM-induced fatigue resulted in physiological and spatiotemporal changes, though the response to fatigue varied considerably between running conditions. These changes resulted in a significant increment only in the downhill energy cost. Incorporating downhill locomotion in the training programmes of ultratrailers may help to improve performance-related physiological and biomechanical parameters.

Effects of Hand Vibration on Motor Output in Chronic Hemiparesis

Background.Muscle vibration has been shown to increase the corticospinal excitability assessed by transcranial magnetic stimulation (TMS) and to change voluntary force production in healthy subjects.Objectives.To evaluate the effect of vibration on corticospinal excitability using TMS and on maximal motor output using maximal voluntary contraction (MVC) in individuals with chronic hemiparesis.Methodology.Nineteen hemiparetic and 17 healthy control subjects participated in this study. Motor evoked potentials (MEPs) and MVC during lateral pinch grip were recorded at first dorsal interosseous muscle in a single session before, during, and after one-minute trials of 80 Hz vibration of the thenar eminence.Results.In hemiparetic subjects, vibration increased MEP amplitudes to a level comparable to that of control subjects and triggered a MEP response in 4 of 7 patients who did not have a MEP at rest. Also, vibration increased the maximal rate of force production (dF/dtmax⁡) in both control and hemiparetic subjects but it did not increase MVC.Conclusion.Motor response generated with a descending cortical drive in chronic hemiparetic subjects can be increased during vibration. Vibration could be used when additional input is needed to reveal motor responses and to increase rate of force generation.

Dynamics of cross-bridge cycling, ATP hydrolysis, force generation, and deformation in cardiac muscle

Despite extensive study over the past six decades the coupling of chemical reaction and mechanical processes in muscle dynamics is not well understood. We lack a theoretical description of how chemical processes (metabolite binding, ATP hydrolysis) influence and are influenced by mechanical processes (deformation and force generation). To address this need, a mathematical model of the muscle cross-bridge (XB) cycle based on Huxley's sliding filament theory is developed that explicitly accounts for the chemical transformation events and the influence of strain on state transitions. The model is identified based on elastic and viscous moduli data from mouse and rat myocardial strips over a range of perturbation frequencies, and MgATP and inorganic phosphate (Pi) concentrations. Simulations of the identified model reproduce the observed effects of MgATP and MgADP on the rate of force development. Furthermore, simulations reveal that the rate of force re-development measured in slack–restretch experiments is not directly proportional to the rate of XB cycling. For these experiments, the model predicts that the observed increase in the rate of force generation with increased Pi concentration is due to inhibition of cycle turnover by Pi. Finally, the model captures the observed phenomena of force yielding suggesting that it is a result of rapid detachment of stretched attached myosin heads.

Computational Model of Cross-Bridge Cycling and Force Generation to Explain the Effect of Metabolites on Cardiac Muscle Mechanics

Despite extensive study over the past six decades the coupling of chemical reaction and mechanical processes in muscle dynamics is not well understood. We lack a theoretical description of how chemical processes (metabolite binding, ATP hydrolysis) influence and are influenced by mechanical processes (deformation and force generation). To address this need, a mathematical model of the muscle crossbridge (XB) cycle based on Huxley's sliding filament theory is developed that explicitly accounts for the chemical transformation events and the influence of strain on state transitions. The model is identified based on elastic and viscous moduli data from mouse and rat myocardial strips over a range of perturbation frequencies, and MgATP and Pi concentrations. Simulations of the identified model reproduce the observed effects of MgATP and MgADP on the rate of force development. Furthermore, simulations reveal that the rate of force re-development measured in slack-restretch experiments is not directly proportional to the rate of XB cycling. For these experiments, the model predicts that the observed increase in the rate of force generation with increased Pi concentration is due to inhibition of cycle turnover by Pi. Finally, the model captures the observed phenomena of force yielding suggesting that it is a result of rapid detachment of stretched attached myosin heads.

Experimental and Computational Approaches to Study Myofilament Structure-Function in Normal and Diseased Muscle

We use a combination of site-directed mutagenesis, protein biochemistry, multi-scale mechanical analysis and computational modeling to study the regulation of normal muscle myofibril contraction and how this is altered in diseases of the sarcomere. This interdisciplinary approach allows us to do detailed structure-function analysis. Mutations in cardiac troponin C (cTnC) that increase Ca2+ binding affinity also increase its affinity for cardiac troponin I (cTnI) and when these cTnC mutants are exchanged into myofibrils or skinned trabeculae, they increase the magnitude and rate of force generation at sub-maximal, but not maximal levels of activation, and can slow the early phase of relaxation. In contrast, cTnC mutations that reduce Ca2+ binding affinity have either no effect or reduce interaction with cTnI, reduce the magnitude and rate of force generation at all levels of Ca2+ and speed relaxation. Molecular Dynamics (MD) simulations show positive correlation between Ca2+ binding affinity and stability of both 1) interaction of Ca2+ with coordinating side chains in site II and 2) the hydrophobic patch of cTnC. Together the data suggest that native cTnC may operate just at the edge of maximal effectiveness. Mutations in cTnI associated with hypertrophic cardiomyopathy increase its affinity for cTnC and also Ca2+ binding affinity of cTnI. Interestingly, they also blunt the ability of cTnI Ser 23/24 phosphorylation to reduce its affinity for cTnC and increase the rate of early phase relaxation. MD simulation studies of whole cTn suggest Ser 23/24 phosphorylation leads to the formation of the intra-subunit interaction between the N-terminus and the inhibitory peptide region of cTnI. We are studying how this, and other intra-molecular interactions may be affected by HCM associated mutations and the contraction and relaxation properties of cardiac muscle. HL65497, HL11197 (MR), 8P41GM103426 (AM).

Myofilament lattice structure in presence of a skeletal myopathy-related tropomyosin mutation

Human tropomyosin mutations deregulate skeletal muscle contraction at the cellular level. One key feature is the slowing of the kinetics of force development. The aim of the present study was to characterize the potential underlying molecular mechanisms by recording and analyzing the X-ray diffraction patterns of human membrane-permeabilized muscle cells expressing a particular β-tropomyosin mutation (E41K). During resting conditions, the d1,0 lattice spacing, Δ1,0 and I1,1 to I1,0 ratio were not different from control values. These results suggest that, in presence of the E41K β-tropomyosin mutation, the myofilament lattice geometry is well maintained and therefore may not have any detrimental influence on the contraction mechanisms and thus, on the rate of force generation.