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Age-related alterations of skeletal muscle are numerous and present inconsistently, and the effect of their interaction on contractile performance can be nonintuitive. Hill-type muscle models predict muscle force according to well-characterised contractile phenomena. Coupled with simple, yet reasonably realistic activation dynamics, such models consist of parameters that are meaningfully linked to fundamental aspects of muscle excitation and contraction. We aimed to illustrate the utility of a muscle model for elucidating relevant mechanisms and predicting changes in output by simulating the individual and combined effects on isometric force of several known ageing-related adaptations. Simulating literature-informed reductions in free Ca2+ concentration and Ca2+ sensitivity generated predictions at odds qualitatively with the characteristic slowing of contraction speed. Conversely, incorporating slower Ca2+ removal or a fractional increase in type I fibre area emulated expected changes; the former was required to simulate slowing of the twitch measured experimentally. Slower Ca2+ removal more than compensated for force loss arising from a large reduction in Ca2+ sensitivity or moderate reduction in Ca2+ release, producing realistic age-related shifts in the force-frequency relationship. Consistent with empirical data, reductions in free Ca2+ concentration and Ca2+ sensitivity reduced maximum tetanic force only slightly, even when acting in concert, suggesting a modest contribution to lower specific force. Lower tendon stiffness and slower intrinsic shortening speed slowed and prolonged force development in a compliance-dependent manner without affecting force decay. This work demonstrates the advantages of muscle modelling for exploring sources of variation and identifying mechanisms underpinning the altered contractile properties of aged muscle. peerReviewed

The single freshly skinned muscle fibre technique was used to investigate Ca2+- and Sr2+-activation properties of skeletal muscle fibres from elderly women (66–90 years). Muscle biopsies were obtained from the vastus lateralis muscle. Three populations of muscle fibres were identified according to their specific Sr2+-activation properties: slow-twitch (type I), fast-twitch (type II) and hybrid (type I/II) fibres. All three fibre types were sampled from the biopsies of 66 to 72 years old women, but the muscle biopsies of women older than 80 years yielded only slow-twitch (type I) fibres. The proportion of hybrid fibres in the vastus lateralis muscle of women of circa 70 years of age (24%) was several-fold greater than in the same muscle of adults (2+- and Sr2+-activation properties of slow-twitch fibres from the two groups of elderly women, but there were differences compared with muscle fibres from young adults with respect to sensitivity to Ca2+, steepness of the activation curves, and characteristics of the fibre-type dependent phenomenon of spontaneous oscillatory contractions (SPOC) (or force oscillations) occurring at submaximal levels of activation. The maximal Ca2+ activated specific force from all the fibres collected from the seven old women use in the present study was significantly lower by 20% than in the same muscle of adults. Taken together these results show there are qualitative and quantitative changes in the activation properties of the contractile apparatus of muscle fibres from the vastus lateralis muscle of women with advancing age, and that these changes need to be considered when explaining observed changes in women’s mobility with aging.

This study sought to identify potential predictors of standing long jump (SLJ) performance using force–time strategy metrics within the unloading, eccentric yielding, eccentric braking, and concentric phases. Fifteen National Collegiate Athletic Association division 1 male soccer players (19 [1] y, 1.81 [0.94] m, 80.3 [22.4] kg) performed 3 maximum-effort SLJs, while 3-dimensional ground reaction force (GRF) data were obtained. Regularized regression models were used to investigate associations between force–time strategy metrics and 2 metrics of SLJ performance (ie, jump distance and modified reactive strength index). Jump height and eccentric yielding time were the only predictors of jump distance that also demonstrated large correlations to jump distance. Anterior–posterior unloading yank, average concentric vertical force, and concentric phase duration were the only predictors of modified reactive strength index that also demonstrated large correlations to modified reactive strength index. To maximize SLJ distance in high-level soccer athletes, human performance practitioners could design interventions to drive changes in strategy to increase jump height and decrease eccentric yielding time. To improve SLJ explosiveness, interventions to drive changes in unloading and concentric force application and decrease concentric time could be emphasized. Importantly, unique variable combinations can be targeted when training for SLJ distance and explosiveness adaptations.

In the repair process of tool moulds, detected damages are removed and the resulting cavities are filled up by a welding process. Due to different types of damage and unknown weld seam properties, each repair case requires an individual machining strategy to ensure high quality. The re-machining step, so-called re-contouring, is currently very time-consuming and leads to experience-dependent workpiece quality. Therefore, this paper presents a specific Kienzle force model combined with optimisation strategies to adapt process parameters and toolpaths as a part of an automated re-contouring process flow. Based on experimental investigations, the force model is generated and used in a material removal simulation to predict the cutting forces according to the local cutting conditions. The method will be validated by re-contouring experiments with welded workpieces.

We propose a new computational method to calculate the storage elastic energy value of surrounding rocks based on numerical simulation and theoretical calculation. By calculating the difference value in energy under different force states and comparing them with the energy level when rock burst occurs, we get the mechanism of rock burst: when roadway and surrounding rocks are in the condition of large ratio bias force field, certain triggering stress causes mass release of the elastic energy of surrounding rocks around the roadway, and when the energy reaches a certain level, rock burst will occur. We also put forward the specific force field conditions and triggering stress values of rock burst, which is of great guiding significance for the mechanism disclosure, monitoring, and control of rock burst.

The aim of the study was to evaluate the possibility to predict the muscle fiber-type proportion in men of different sports specialization by testing the maximal torque production by knee extensors at different velocities. For this reason the proportion of fast- and slow-twitch muscle fibers (MFs) in m. vastus lateralis of 23 athletes (11 endurance and 12 power athletes), as well the maximal torque production of knee extensors at various angular velocities in isokinetic mode were determined. The group of strength trained athletes significantly exceeded the group of endurance trained athletes in body mass, body mass index, volume of the m. quadriceps femoris, maximum torque production, and specific force at angular velocities 30, 180 and 300 degrees per second. In contrast to cross-sectional area (CSA) of slow-twitch MFs, the average CSA of fast-twitch MFs and the proportion of fast-twitch MFs in the group of power athletes significantly exceeded those in the group of endurance athletes. In the combined group of volunteers (n = 23), the proportion of fast-twitch MFs significantly correlated with the torque production at high angular velocities (r = 0.51 and p = 0.01 at 180 deg/s; r = 0.47 and p = 0.02 at 300 deg/s). We did not find any correlation between these parameters in the separate groups of power and endurance athletes. The results indicate a low accuracy in predicting the proportion of fast-twitch MF in m. vastus lateralis in athletes using the maximal torque production of knee extensors at different angular velocities. Significant correlation between the proportion of fast-twitch MF and maximal torque at high angular velocities in the general group (n = 23) was due to the presence of two significantly different subgroups.

Volumetric muscle loss (VML) is traumatic, degenerative, or surgical loss of skeletal muscle that exceeds the regenerative capacity of the remaining muscle, thus resulting in impaired muscle function. In humans, the loss of 30% or more mass of any one muscle will result in permanent structural and functional loss. Current VML repair treatments are limited by donor site morbidity and graft tissue availability, necessitating alternative muscle graft sources. To address this need, our lab has fabricated tissue-engineered skeletal muscle units (SMUs) for implantation into a 30 % VML model in the tibialis anterior (TA) muscle of rat. Previous results showed that after 28 days in vivo, muscle with a 30% VML repaired with our SMUs produced significantly more force than muscle with acute VML. But repair with our SMU did not fully restore muscle force production to that of native muscle. Thus, we hypothesized that more time for in vivo tissue regeneration would allow for greater force recovery. Therefore, the purpose of this study was to examine the long-term (3-month) effects of our SMUs on a 30% VML repair. We also assessed the effects of reinnervation by redirecting a branch of the peroneal nerve to the repair site. Thirty-nine, 2-month old female F344 rats were separated into a nonsurgical control group (n=5) and four surgical experimental groups (VML Only, n=5; VML+Nerve Redirect, n=6; VML+SMU, n=5; VML+SMU+ Nerve Redirect, n=8). Experimental rats were allowed a 3-month recovery period post-surgery before undergoing in situ force testing of the surgical (left) TA. The left TA of the control animals also underwent in situ force testing. Finally, the surgical (left) and contralateral (right) TAs of the experimental animals, as well as the left TA of the control animals, were explanted for histological analysis. Results for specific force showed that while all groups recovered specific forces similar to that of native muscle, the two SMU groups had significantly higher specific forces, on average, compared to the uninjured control group. Histological staining showed small muscle fibers in the repair site in animals that received an SMU. The average cross-sectional area of the native fibers just outside the area of repair (or the equivalent area in control animals) was not significantly different between groups, indicating that hypertrophy of remaining fibers did not contribute to the recovery of force following the VML. Our results suggest that following a 30% VML of the TA muscle, all surgical groups were able to recover TA mass, maximum tetanic and specific force production. Thus, creating a 30% VML in the TA in a rat model is not enough a sufficient VML to produce the sustained VML seen in humans following similar 30% loss of muscle volume.

This paper presents a novel optimal Motion Cueing Algorithm (MCA) to control the rotations of a Human Centrifuge (HC) and achieve the best simulation of a SpaceCraft (SC) motion. Relations of the specific forces sensed by astronauts of the SC and the HC have been derived and linearized. A Linear Quadratic Regulator (LQR) controller is implemented for the problem which tends to minimize the error between the two sensed specific forces as well as control input in a cost function. It results in control inputs of the HC to generate its sensed specific force as close as possible to the one in the SC. The algorithm is implemented for both linearized and nonlinear portions of a US space shuttle mission trajectory as a verification using MATLAB. In longitudinal direction, the proposed MCA, works well when the acceleration is less than 2g in which the tracking error does not exceed 12%. In lateral direction the tracking is much better even in nonlinear region since the error remains less than 7% for tilting up to 50°. Finally, the effect of weight matrixes in the LQR cost function on overall weight and power of the HC motion system is discussed.

Skeletal muscle myopathies represent a common non-pulmonary manifestation of influenza infection, leading to reduced physical function and hospitalization in older adults. However, underlying mechanisms remain poorly understood. Our study examined the effects of influenza virus A pulmonary infection on contractile function at the cellular (single fiber) and molecular (myosin-actin interactions and myofilament properties) levels in soleus and extensor digitorum longus muscles of aged (20 months) C57BL/6 male mice that were healthy or flu-infected for 7 (7-days post-infection; 7-DPI) or 12 days (12-DPI). Cross-sectional area (CSA) of myosin heavy chain (MHC) IIA and IIB fibers was reduced at 12-DPI relative to 7-DPI and healthy. Maximal isometric force in MHC IIA fibers was also reduced at 12-DPI relative to 7-DPI and healthy, resulting in no change in specific force (maximal isometric force divided by CSA). In contrast, MHC IIB fibers produced greater isometric force and specific force at 7-DPI compared to 12-DPI or healthy. The increased specific force in MHC IIB fibers was likely due to greater myofilament lattice stiffness and/or an increased number or stiffness of strongly bound myosin-actin cross-bridges. At the molecular level, cross-bridge kinetics were slower in MHC IIA fibers with infection, while changes in MHC IIB fibers were largely absent. In both fiber types, greater myofilament lattice stiffness was positively related to specific force. This study provides novel evidence that cellular and molecular contractile function is impacted by influenza infection in a fiber type-specific manner, suggesting potential molecular mechanisms to help explain the impact of flu-induced myopathies.

The number of patients with chronic obstructive pulmonary disease (COPD), a typical respiratory disorder, is rapidly increasing globally. The purpose of this study was to determine the effects of appropriate-intensity treadmill exercise on skeletal muscle and respiratory functions in a rat model of emphysema. Twenty-one Wistar rats were randomly divided into three groups: the sham (SH) group, pulmonary emphysema (PE) group, and emphysema + exercise (EX) group. Cigarette smoke solution and lipopolysaccharide were intratracheally administered for 4 weeks in the PE and EX groups. The rats in the EX group were made to run on treadmills in the latter 2 weeks of the experiment. Lung tissue was stained with anti-macrophage antibodies; the specific force (contractile force per unit cross-sectional area) of the diaphragm and hind-limb muscles was measured, and blood was analyzed for serum cytokine levels. Many macrophages were observed in the lung tissue of the PE group. In the EX group, the population of macrophages was smaller, and the specific force of the diaphragm and extensor digitorum longus muscles was higher than in the PE group. Moreover, the degree of inflammation in the pulmonary tissue was reduced in the EX group. These results suggest that adaptive exercise may improve not only respiratory and muscle functions but also inflammation of the pulmonary tissue associated with emphysema.

Методом скінченних елементів створені математичні моделі і проведено дослідження прямого і зворотного способів гарячого обтиску в матриці спеціального профілю порожнистих заготовок із високовуглецевої сталі зі змінною товщиною стінки по висоті. Використана пластична модель металу і циліндричні координати. Розрахунковим шляхом встановлено форму і розміри вихідної заготовки для обтиску, які забезпечили необхідні розміри виробу. Перед обтиском здійснювався нагрів частини заготовки по висоті, яка підлягала деформуванню в матриці. Застосування матриці спеціального профілю з деформуючою поверхнею, виконаної з кільцевими виступами, дозволило отримати виріб за один перехід завдяки зменшенню впливу сил тертя при формоутворенні. Визначена швидкість деформування для дотримання режиму гарячої деформації протягом обтиску. Встановлено залежність осьового зусилля на деформуючому інструменті від переміщення пуансонів і розподілу питомих зусиль на контактуючих поверхнях. Застосування прямого обтиску призводить до зниження силових режимів і питомих зусиль на інструменті. Визначено кінцевий напружено-деформований стан металу, форму і розміри виробу. По розподілу інтенсивності деформації проведена оцінка пропрацювання структури металу пластичною деформацією. На основі даних моделювання розроблена конструкція загального виду штампового оснащення для виконання прямого обтиску. Using the finite element method, mathematical models were created and studies were carried out of direct and reverse methods of hot crimping in a matrix of a special profile of hollow workpieces made of high-carbon steel with a variable wall thickness along the height. A plastic model of metal and cylindrical coordinates are used. By calculation, the shape and dimensions of the initial workpiece for crimping were established, which provided the required dimensions of the product. Before crimping, a part of the billet was heated along the height, which was subject to deformation in the matrix. The use of a matrix of a special profile with a deforming surface made with annular protrusions made it possible to obtain a product in one step due to a decrease in the influence of friction forces during shaping. The deformation rate is determined to comply with the hot deformation mode during the crimping. The depend- ences of the axial force on the deforming tool on the movement of punches and the distribution of specific forces on the contact surfaces are established. The use of direct crimping leads to a decrease in forces modes and specific forces on the tool. The final stress-strain state of the metal, the shape and dimensions of the product are determined. According to the distribution of strain intensity, an assessment was made of the elaboration of the metal structure by plastic deformation. Based on the simulation data, a design of the general view of the die tooling for direct crimping has been developed.

Across insects, wing shape and size have undergone dramatic divergence even in closely related sister groups. However, we do not know how morphology changes in tandem with kinematics to support body weight within available power and how the specific force production patterns are linked to differences in behaviour. Hawkmoths and wild silkmoths are diverse sister families with divergent wing morphology. Using three-dimensional kinematics and quasi-steady aerodynamic modelling, we compare the aerodynamics and the contributions of wing shape, size and kinematics in 10 moth species. We find that wing movement also diverges between the clades and underlies two distinct strategies for flight. Hawkmoths use wing kinematics, especially high frequencies, to enhance force and wing morphologies that reduce power. Silkmoths use wing morphology to enhance force, and slow, high-amplitude wingstrokes to reduce power. Both strategies converge on similar aerodynamic power and can support similar body weight ranges. However, inter-clade within-wingstroke force profiles are quite different and linked to the hovering flight of hawkmoths and the bobbing flight of silkmoths. These two moth groups fly more like other, distantly related insects than they do each other, demonstrating the diversity of flapping flight evolution and a rich bioinspired design space for robotic flappers.

Synergistic ablation (SA) is widely used to induce muscle hypertrophy in rodent studies. However, it has been demonstrated that SA-induced compensatory hypertrophy induces increases in maximum isometric force that are smaller in magnitude than the increase in muscle cross-sectional area, suggesting a reduction in the specific force production due to intrinsic contractile dysfunction in the hypertrophied fibers. Here, by using the mechanical skinned fibers, we investigated the mechanisms behind the reduction in specific force in the compensatory hypertrophied muscles. Rats had unilateral surgical ablation of the gastrocnemius and soleus muscles to induce the compensatory hypertrophy in the plantaris muscles. Two wk after surgery, the mean fiber diameter was increased by 19% in the SA group compared with the contralateral control (CNT) group. In contrast, compared with the CNT group, both the depolarization-induced force (−51%) and the Ca2+-activated maximum specific force (−32%) were markedly reduced in skinned fibers from the SA group. These deleterious functional alterations were accompanied by decreases in the amount of DHPRα1, RYR, junctophilin 1, and SH3 and cysteine-rich domain 3 (STAC3) in SA muscles. Thus, these data clearly show that SA induces not only an increase in skeletal muscle fiber hypertrophy but also leads to a reduction in the intrinsic contractile dysfunction due to the excitation–contraction uncoupling and impaired force-generating capacity.

Many tasks require the skilled interaction of both hands, such as eating with knife and fork or keyboard typing. However, our understanding of the behavioural and neurophysiological mechanisms underpinning bimanual motor learning is still sparse. Here, we aimed to address this by first characterising learning-related changes of different levels of bimanual interaction and second investigating how beta tACS modulates these learning-related changes. To explore early bimanual motor learning, we designed a novel bimanual motor learning task. In the task, a force grip device held in each hand (controlling x- and y-axis separately) was used to move a cursor along a path of streets at different angles (0°, 22.5°, 45°, 67.5°, and 90°). Each street corresponded to specific force ratios between hands, which resulted in different levels of hand interaction, i.e., unimanual (Uni, i.e., 0°, 90°), bimanual with equal force (Bieq, 45°), and bimanual with unequal force (Biuneq 22.5°, 67.5°). In experiment 1, 40 healthy participants performed the task for 45 min with a minimum of 100 trials. We found that the novel task induced improvements in movement time and error, with no trade-off between movement time and error, and with distinct patterns for the three levels of bimanual interaction. In experiment 2, we performed a between-subjects, double-blind study in 54 healthy participants to explore the effect of phase synchrony between both sensorimotor cortices using tACS at the individual’s beta peak frequency. The individual’s beta peak frequency was quantified using electroencephalography. 20 min of 2 mA peak-to-peak amplitude tACS was applied during task performance (40 min). Participants either received in-phase (0° phase shift), out-of-phase (90° phase shift), or sham (3 s of stimulation) tACS. We replicated the behavioural results of experiment 1, however, beta tACS did not modulate motor learning. Overall, the novel bimanual motor task allows to characterise bimanual motor learning with different levels of bimanual interaction. This should pave the way for future neuroimaging studies to further investigate the underlying mechanism of bimanual motor learning.

Force produced by the muscle during contraction is applied to the tendon and distributed through the cross-sectional area (CSA) of the tendon. This ratio of force to the tendon CSA is quantified as the tendon mechanical property of stress. Stress is traditionally calculated using the resting tendon CSA; however, this does not take into account the reductions in the CSA resulting from tendon elongation during the contraction. It is unknown if calculating the tendon stress using instantaneous CSA during a contraction significantly increases the values of in vivo distal biceps brachii (BB) tendon stress in humans compared to stress calculated with the resting CSA. Nine young (22 ± 1 years) and nine old (76 ± 4 years) males, and eight young females (21 ± 1 years) performed submaximal isometric elbow flexion tracking tasks at force levels ranging from 2.5 to 80% maximal voluntary contraction (MVC). The distal BB tendon CSA was recorded on ultrasound at rest and during the submaximal tracking tasks (instantaneous). Tendon stress was calculated as the ratio of tendon force during contraction to CSA using the resting and instantaneous measures of CSA, and statistically evaluated with multi-level modeling (MLM) and Johnson–Neyman regions of significance tests to determine the specific force levels above which the differences between calculation methods and groups became statistically significant. The tendon CSA was greatest at rest and decreased as the force level increased (p < 0.001), and was largest in young males (23.0 ± 2.90 mm2) followed by old males (20.87 ± 2.0 mm2) and young females (17.08 ± 1.54 mm2) (p < 0.001) at rest and across the submaximal force levels. Tendon stress was greater in the instantaneous compared with the resting CSA condition, and young males had the greatest difference in the values of tendon stress between the two conditions (20 ± 4%), followed by old males (19 ± 5%), and young females (17 ± 5%). The specific force at which the difference between the instantaneous and resting CSA stress values became statistically significant was 2.6, 6.6, and 10% MVC for old males, young females, and young males, respectively. The influence of using the instantaneous compared to resting CSA for tendon stress is sex-specific in young adults, and age-specific in the context of males. The instantaneous CSA should be used to provide a more accurate measure of in vivo tendon stress in humans.

BACKGROUND: Diaphragm dysfunction with increased reactive oxygen species (ROS) occurs within 72 hrs post-myocardial infarction (MI) in mice and may contribute to loss of inspiratory maximal pressure and endurance in patients. METHODS: We used wild-type (WT) and whole-body Nox4 knockout (Nox4KO) mice to measure diaphragm bundle force in vitro with a force transducer, mitochondrial respiration in isolated fiber bundles with an O(2) sensor, mitochondrial ROS by fluorescence, mRNA (RT-PCR) and protein (immunoblot), and fiber size by histology 72 hrs post-MI. RESULTS: MI decreased diaphragm fiber cross-sectional area (CSA) (~15%, p = 0.015) and maximal specific force (10%, p = 0.005), and increased actin carbonylation (5–10%, p = 0.007) in both WT and Nox4KO. Interestingly, MI did not affect diaphragm mRNA abundance of MAFbx/atrogin-1 and MuRF-1 but decreased Nox4KO decreased it by 20–50% (p < 0.01). Regarding the mitochondria, MI and Nox4KO decreased the protein abundance of citrate synthase and subunits of electron transport system (ETS) complexes and increased mitochondrial O(2) flux (JO(2)) and H(2)O(2) emission (JH(2)O(2)) normalized to citrate synthase. Mitochondrial electron leak (JH(2)O(2)/JO(2)) in the presence of ADP was lower in Nox4KO and not changed by MI. CONCLUSIONS: Our study shows that the early phase post-MI causes diaphragm atrophy, contractile dysfunction, sarcomeric actin oxidation, and decreases citrate synthase and subunits of mitochondrial ETS complexes. These factors are potential causes of loss of inspiratory muscle strength and endurance in patients, which likely contribute to the pathophysiology in the early phase post-MI. Whole-body Nox4KO did not prevent the diaphragm abnormalities induced 72 hrs post-MI, suggesting that systemic pharmacological inhibition of Nox4 will not benefit patients in the early phase post-MI.

Chemically skinned fibres allow the study of human muscle contractile function in vitro. A particularly important parameter is specific force (SF), that is, maximal isometric force divided by cross-sectional area, representing contractile quality. Although SF varies substantially between studies, the magnitude and cause of this variability remains puzzling. Here, we aimed to summarize and explore the cause of variability in SF between studies. A systematic search was conducted in Medline, Embase and Web of Science databases in June 2020, yielding 137 data sets from 61 publications which studied healthy, young adults. Five-fold differences in mean SF data were observed. Adjustments to the reported data for key methodological differences allowed between-study comparisons to be made. However, adjustment for fibre shape, swelling and sarcomere length failed to significantly reduce SF variance (I2 = 96%). Interestingly, grouping papers based on shared authorship did reveal consistency within research groups. In addition, lower SF was found to be associated with higher phosphocreatine concentrations in the fibre activating solution and with Triton X-100 being used as a skinning agent. Although the analysis showed variance across the literature, the ratio of SF in single fibres containing myosin heavy chain isoforms IIA or I was found to be consistent across research groups. In conclusion, whilst the skinned fibre technique is reliable for studying in vitro force generation of single fibres, the composition of the solution used to activate fibres, which differs between research groups, is likely to heavily influence SF values.

Study design Basic science, experimental animal study. Objective To determine the effects of BTX-A injections on the mechanical properties of skinned muscle fibres (cells) of rabbit paraspinal muscles. Summary of background data Botulinum toxin type A (BTX-A) has been widely used in the treatment of disorders of muscle hyperactivity, such as spasticity, dystonia, and back pain. However, BTX-A injection has been shown to cause muscle atrophy, fat infiltration, and decreased force output in target muscles, but its potential effects on the contractile machinery and force production on the cellular level remain unknown. Methods Nineteen-month-old, male New Zealand White Rabbits received either saline or BTX-A injections into the paraspinal muscles, equally distributed along the left and right sides of the spine at T12, L1, and L2 at 0, 8, 12, 16, 20, and 24 weeks. Magnetic resonance imaging was used to quantify muscle cross-sectional area and structural changes before and at 28 weeks following the initial injection. Skinned fibres isolated from the paraspinal muscles were tested for their active and passive force-length relationships, unloaded shortening velocity and myosin heavy chain isoforms. Results BTX-A injections led to significant fat infiltration within the injected muscles and a greater proportion of IIa to IIx fibres. Isolated fast fibres from BTX-A injected animals had lower active force and unloaded shortening velocity compared to fibres from saline-injected control animals. Force and velocity properties were not different between groups for the slow fibres. Conclusion Injection of BTX-A into the paraspinal rabbit muscles leads to significant alterations in the contractile properties of fast, but not slow, fibres.Level of Evidence: N/A.

Calpain activation has been postulated as a potential contributor to the loss of muscle mass and function associated with both aging and disease, but limitations of previous experimental approaches have failed to completely examine this issue. We hypothesized that mice overexpressing calpastatin (CalpOX), an endogenous inhibitor of calpain, solely in skeletal muscle would show an amelioration of the aging muscle phenotype. We assessed four groups of mice (age in months): 1) young wild type (WT; 5.71 ± 0.43), 2) young CalpOX (5.6 ± 0.5), 3) old WT (25.81 ± 0.56), and 4) old CalpOX (25.91 ± 0.60) for diaphragm and limb muscle (extensor digitorum longus, EDL) force frequency relations. Aging significantly reduced diaphragm and EDL peak force in old WT mice, and decreased the force-time integral during a fatiguing protocol by 48% and 23% in aged WT diaphragm and EDL, respectively. In contrast, we found that CalpOX mice had significantly increased diaphragm and EDL peak force in old mice, similar to that observed in young mice. The impact of aging on the force-time integral during a fatiguing protocol was abolished in the diaphragm and EDL of old CalpOX animals. Surprisingly, we found that CalpOX had a significant impact on longevity, increasing median survival from 20.55 mo in WT mice to 24 mo in CalpOX mice (P = 0.0006). NEW & NOTEWORTHY This is the first study to investigate the role of calpastatin overexpression on skeletal muscle specific force in aging rodents. Muscle-specific overexpression of calpastatin, the endogenous calpain inhibitor, prevented aging-induced reductions in both EDL and diaphragm specific force and, remarkably, increased life span. These data suggest that diaphragm dysfunction in aging may be a major factor in determining longevity. Targeting the calpain/calpastatin pathway may elucidate novel therapies to combat skeletal muscle weakness in aging.

Sepsis induces a myopathy characterized by loss of muscle mass and weakness. Septic patients undergo prolonged periods of limb muscle disuse due to bed rest. The contribution of limb muscle disuse to the myopathy phenotype remains poorly described. To characterize sepsis‐induced myopathy with hindlimb disuse, we combined the classic sepsis model via cecal ligation and puncture (CLP) with the disuse model of hindlimb suspension (HLS) in mice. Male C57bl/6j mice underwent CLP or SHAM surgeries. Four days after surgeries, mice underwent HLS or normal ambulation (NA) for 7 days. Soleus (SOL) and extensor digitorum longus (EDL) were dissected for in vitro muscle mechanics, morphological, and histological assessments. In SOL muscles, both CLP+NA and SHAM+HLS conditions elicited ~20% reduction in specific force (p, This study shows the impact of skeletal muscle disuse on sepsis‐induced myopathy in mice. Developed with Biorender software.

IntroductionLittle is known about potential differences in contractile properties of muscle fibers of the same type in arms and legs. Accordingly, the present study was designed to compare the force-generating capacity and Ca2+ sensitivity of fibers from arm and leg muscles of highly trained cross-country skiers.MethodSingle muscle fibers of m. vastus lateralis and m. triceps brachii of eight highly trained cross-country skiers were analyzed with respect to maximal Ca2+-activated force, specific force and Ca2+ sensitivity.ResultThe maximal Ca2+-activated force was greater for myosin heavy chain (MHC) II than MHC I fibers in both the arm (+62%, P < 0.001) and leg muscle (+77%, P < 0.001), with no differences between limbs for each MHC isoform. In addition, the specific force of MHC II fibers was higher than that of MHC I fibers in both arms (+41%, P = 0.002) and legs (+95%, P < 0.001). The specific force of MHC II fibers was the same in both limbs, whereas MHC I fibers from the m. triceps brachii were, on average, 39% stronger than fibers of the same type from the m. vastus lateralis (P = 0.003). pCa50 was not different between MHC I and II fibers in neither arms nor legs, but the MHC I fibers of m. triceps brachii demonstrated higher Ca2+ sensitivity than fibers of the same type from m. vastus lateralis (P = 0.007).ConclusionComparison of muscles in limbs equally well trained revealed that MHC I fibers in the arm muscle exhibited a higher specific force-generating capacity and greater Ca2+ sensitivity than the same type of fiber in the leg, with no such difference in the case of MHC II fibers. These distinct differences in the properties of fibers of the same type in equally well-trained muscles open new perspectives in muscle physiology.

Changes in stiffness or extensibility of the muscle or muscle–tendon unit with aging could lead to impaired function and an increased vulnerability to injury. We aimed to investigate the passive force and viscoelastic properties of single muscle fibers in older adults. Seven older adults (mean age 79.0 ± 3.8 years) and 10 young control (mean age 25.6 ± 4.5 years) were recruited. Biopsy specimens were obtained percutaneously from m. vastus lateralis and skinned single fibers were used for the experiments. Slack tests were performed to determine maximal force and maximal unloaded shortening velocity. Passive force was measured in pCa 9.0 solution using a stepwise stretch technique with increment of sarcomere length from 2.4 to 4.2 µm. Myosin heavy chain (MHC) isoform was determined by sodium dodecyl sulfate–polyacrylamide gel electrophoresis. Specific force was calculated as maximal force divided by cross-sectional area. Passive force, peak passive force, time to half stress relaxation (T1/2) and force decay index (a force time integral under a stress relaxation curve) were measured. No difference between the groups were found in specific force and shortening velocity. Passive force and peak passive force were greater in both MHC I and IIa fibers of older adults (p

This study aimed to examine the distribution and contractile properties of single muscle fiber sex/myosin heavy chain (MHC) type-related differences and to evaluate the correlation of cross-sectional area (CSA) and specific force (SF) in a single muscle fiber. Six young men and six young women were participated in this study. Muscle sample was obtained from vastus lateralis muscle. To examine potential gender differences within each fiber contractile properties (CSA, maximal isometric force, SF, maximal shortening velocity) and relationship between CSA and SF of single fiber using Pearson correlation. After mechanical measurements, single muscle fiber determined MHC isoforms using silver stain. MHC isoform composition did not differ by sex (chi-square=6.978, P=0.073). There were sex-related differences in CSA and maximal isometric force (P0.05). Related to SF and maximal shortening velocity, there were no sex-related differences only fiber type-related differences (P

This article describes the results of a study that looked at the stress state and the specific force or contact pressure through the application of the slip line method and computer simulation (i.e. using the Deform 3D software package) when a workpiece was subjected to severe plastic deformation (SPD) in a special closed die. SPD is achieved when a flat punch is embedded in a round workpiece enclosed in the die and alternately compressed by a ring-shaped punch. Analysis of the results shows that compressive stresses prevail in the deformation zone resulting in the production of blanks with ultrafine-grained and/or nanostructure, as well as high mechanical properties. The relative discrepancy between the results obtained through the slip line method and those obtained through modelling in Deform 3D was about 1.3% indicating that the results can be considered reliable. It should be noted that this closed-die technique can be used to produce such products as gears, i.e. heavy-duty parts.

A numerical study is carried out to investigate the influence of a sudden change of the specific force on a three-floated gyroscope with a rotor supported on gas-lubricated bearings. The interference torque is calculated to evaluate the influence by modeling the transient behavior of the rotor-bearing system. In combination with dynamic equations of the rotor displacement, the Reynolds equation is solved on the surface of spiral-grooved conical bearings. It is assumed that a steady state has been obtained with a constant specific force, and then the specific force is suddenly changed and maintained constant after that. Responses of the sudden change are obtained by solving the equations. Numerical results show that the direction of the sudden change of the specific force is the main factor which influences the interference torque curve. With a sudden change along the input direction, the interference torque fluctuation has a constant frequency and a decreasing amplitude. With a sudden change along the output direction, the interference torque fluctuates in a small range. With a sudden change along the spin direction, the change of the interference torque combines a fluctuation and a gradually-changing quasi-equilibrium value. This study provides a supplement to the steady-state error model of the three-floated gyroscope. Keywords: Conical bearing, Gas lubricated bearings, Interference torque, Rotor-bearing system, Three-floated gyroscope

Molecular dynamics (MD) simulation has become a powerful tool for studying the structures and functional mechanisms of biomolecules, and its reliability crucially depends on the accuracy of underlying force fields. This perspective describes our recent efforts to develop more accurate protein force fields by improving the description of intrinsic conformational preferences of amino acid residues using residue-specific dihedral-angle-related parameters. Both backbone and side-chain conformational distributions and their coupling were optimized to fit those from a protein coil library. The resulting force fields RSFF1 and RSFF2 have been found to be more accurate than popular protein force fields, in reproducing experimental structural data of various peptides and proteins. They have also been successfully used in studying folding mechanisms and refinement of structure models. Further methodology developments related to intrinsically disordered proteins (RSFF2+) and a more universal implementation (RSFF2C) based on CMAP potentials are also described.

Contains fulltext : 205507.pdf (Publisher’s version ) (Open Access) Atrophy and fatty infiltration are important causes of muscle weakness in inclusion body myositis (IBM). Muscle weakness can also be caused by reduced specific force; i.e. the amount of force generated per unit of residual muscle tissue. This study investigates in vivo specific force of the quadriceps and ex vivo specific force of single muscle fibers in patients with IBM. We included 8 participants with IBM and 12 healthy controls, who all underwent quantitative muscle testing, quantitative MRI of the quadriceps and paired muscle biopsies of the quadriceps and tibialis anterior. Single muscle fibers were isolated to measure muscle fiber specific force and contractile properties. Both in vivo quadriceps specific force and ex vivo muscle fiber specific force were reduced. Muscle fiber dysfunction was accompanied by reduced active stiffness, which reflects a decrease in the number of attached actin-myosin cross-bridges during activation. Myosin concentration was reduced in IBM fibers. Because reduced specific force contributes to muscle weakness in patients with IBM, therapeutic strategies that augment muscle fiber strength may provide benefit to patients with IBM.

Background: Human aging is characterized by a chronic, low-grade inflammation suspected to contribute to reductions in skeletal muscle size, strength, and function. Inflammatory cytokines, such as interleukin-6 (IL-6), may play a role in the reduced skeletal muscle adaptive response seen in older individuals. Objectives: To investigate relationships between circulating IL-6, skeletal muscle health and exercise adaptation in mobility-limited older adults. Design: Randomized controlled trial. Setting: Exercise laboratory on the Health Sciences campus of an urban university. Participants: 99 mobility-limited (Short Physical Performance Battery (SPPB) ≤9) older adults. Intervention: 6-month structured physical activity with or without a protein and vitamin D nutritional supplement. Measurements: Circulating IL-6, skeletal muscle size, composition (percent normal density muscle tissue), strength, power, and specific force (strength/CSA) as well as physical function (gait speed, stair climb time, SPPB-score) were measured pre- and post-intervention. Results: At baseline, Spearman’s correlations demonstrated an inverse relationship (P1.36 pg/ml). Moreover, baseline IL-6 was inversely associated (P

Background Four mechanical alignment force targets are used to predict early patient-reported outcomes and/or to indicate a balanced TKA. For surgeons who use kinematic alignment, there are no reported force targets. To date the usefulness of these mechanical alignment force targets with kinematic alignment has not been reported nor has a specific force target for kinematic alignment been identified. Questions/purposes (1) Does hitting one of four mechanical alignment force targets proposed by Gustke, Jacobs, Meere, and Menghini determine whether a patient with a kinematically aligned TKA had better patient-reported Oxford Knee and WOMAC scores at 6 months? (2) Can a new force target be identified for kinematic alignment that determines whether the patient had a good/excellent Oxford Knee Score of ≥ 34 points (48 best, 0 worst)? Methods Between July 2017 and November 2017, we performed 148 consecutive primary TKAs of which all were treated with kinematic alignment using 10 caliper measurements and verification checks. A total of 68 of the 148 (46%) TKAs performed during the study period had intraoperative measurements of medial and lateral tibial compartment forces during passive motion with an instrumented tibial insert and were evaluated in this retrospective study. Because the surgeon and surgical team were blinded from the display showing the compartment forces, there was no attempt to hit a mechanical alignment force target when balancing the knee. The Oxford Knee Score and WOMAC score measured patient-reported outcomes at 6 months postoperatively. For each mechanical alignment force target, a Wilcoxon rank-sum test determined whether patients who hit the target had better outcome scores than those who missed. An area under the curve (AUC) analysis tried to identify a new force target for kinematic alignment at full extension and 10°, 30°, 45°, 60°, 75°, and 90° of flexion that predicted whether patients had a good/excellent Oxford Knee Score, defined as a score of ≥ 34 points. Results Patients who hit or missed each of the four mechanical alignment force targets did not have higher or lower Oxford Knee Scores and WOMAC scores at 6 months. Using the Gustke force target as a representative example, the Oxford Knee Score of 41 ± 6 and WOMAC score of 13 ± 11 for the 31 patients who hit the target were not different from the Oxford Knee Score of 39 ± 8 (p = 0.436) and WOMAC score of 17 ± 17 (p = 0.463) for the 37 patients who missed the target. The low observed AUCs (from 0.56 to 0.58) at each of these flexion angles failed to identify a new kinematic alignment force target associated with a good/excellent (≥ 34) Oxford Knee Score. Conclusions Tibial compartment forces comparable to those reported for the native knee and insufficient sensitivity of the Oxford Knee and WOMAC scores might explain why mechanical alignment force targets were not useful and a force target was not identified for kinematic alignment. Intraoperative sensors may allow surgeons to measure forces very precisely in the operating room, but that level of precision is not called for to achieve a good/excellent result after calipered kinematically aligned TKA, and so its use may simply add expense and time but does not improve the results from the patient's viewpoint. Level of evidence Level III, therapeutic study.

By incorporating pH responsive i-motif elements, we have constructed DNA origami nanosprings that respond to pH changes in the environment. Using an innovative force jump approach in optical tweezers, we have directly measured the spring constants and dynamic recoiling responses of the DNA nanosprings under different forces. These DNA nanosprings exhibited 3 times slower recoiling rates compared to duplex DNA backbones. In addition, we observed two distinct force regions which show different spring constants. In the entropic region below 2 pN, a spring constant of ∼0.03 pN nm-1 was obtained, whereas in the enthalpic region above 2 pN, the nanospring was 17 times stronger (0.5 pN nm-1). The force jump gave a more accurate measurement on nanospring constants compared to regular force ramping approaches, which only yielded an average spring constant in a specific force range. Compared to the reported DNA origami nanosprings with a completely different design, our nanospring is up to 50 times stiffer. The drastic increase in the spring constant and the pH responsive feature allow more robust applications of these nanosprings in many mechanobiological processes.

Ultrasonography advantageously measures skeletal muscle size and quality, but some muscles may be too large to capture with standardized brightness mode (B-mode) imaging. Panoramic ultrasonography can capture more complete images and may more accurately measure muscle size. We investigated measurements made using panoramic compared to B-mode ultrasonography images of the rectus femoris with muscular performance. Concurrently, protein intake plays an important role in preventing sarcopenia, therefore, we also sought to investigate the association between animal-based protein intake (ABPI) and muscular performance. Ninety-one middle-aged adults were recruited. Muscle cross-sectional area (CSA) and thickness were obtained using B-mode and panoramic ultrasound and analyzed with Image J software. Muscular performance was assessed using isokinetic dynamometry, a 30-s chair test, and handgrip strength. Three-day food diaries estimated dietary intakes. Linear regression models determined relationships between measures from ultrasonography and muscular performance. Mixed linear models were used to evaluate the association between ABPI and muscular performance. Muscle CSA from panoramic ultrasonography and ABPI were positively associated with lower-body strength (β ± S.E., CSA, 42.622 ± 20.024, p = 0.005, ABPI, 65.874 ± 19.855, p = 0.001), lower-body endurance (β ± S.E., CSA, 595 ± 200.221, p = 0.001, ABPI, 549.944 ± 232.478, p = 0.020), and handgrip strength (β ± S.E., CSA, 6.966 ± 3.328, p = 0.004, ABPI, 0.349 ± 0.171, p = 0.045). Panoramic ultrasound shows promise as a method for assessing sarcopenia. ABPI is related to better muscular performance.

New findings What is the central question of this study? The (dystrophin-deficient) muscles of mdx mice generate less contractile force per cross-sectional area (specific force) than those of healthy wild-type mice. We test the influence of Muscle Specific Kinase (MuSK) upon the properties of the tibialis anterior (TA) muscle in mdx mice. What is the main finding and its importance? Injection of adeno-associated viral vector encoding MuSK into the TA muscle of young mdx mice increased the specific force of the muscle, suggesting the MuSK signalling system has the potential to restore healthy growth to dystrophin-deficient muscles. Abstract In the mdx mouse model of Duchenne muscular dystrophy, muscle fibres are fragile and prone to injury and degeneration. Compared to wild-type mice, muscles of mdx mice also develop less specific force (contractile force/cross-sectional area). We recently reported that injecting adeno-associated viral vector encoding muscle specific kinase (AAV-MuSK) into muscles of mdx mice increased utrophin expression and made the muscles more resistant to acute stretch-induced injury. Here we injected AAV-MuSK unilaterally into the tibialis anterior muscle of mdx mice at a younger age (4-weeks), and recorded contraction force from the muscles in situ at 12-weeks of age. Compared to contralateral empty-vector control muscles, muscles injected with AAV-MuSK produced 28% greater specific force (p = 0.0005). They did not undergo the compensatory hypertrophy that normally occurs in muscles of mdx mice. Injection of AAV encoding rapsyn (a downstream effector of MuSK signalling) caused no such improvement in muscle strength. Muscles injected with AAV-MuSK displayed a 10% reduction in the number of fibres with centralised nuclei (p = 0.0015). Our results in mdx mice suggest that elevating the expression of MuSK can reduce the incidence of muscle fibre regeneration and improve the strength of dystrophin-deficient muscles. This article is protected by copyright. All rights reserved.

Contains fulltext : 229514.pdf (Publisher’s version ) (Open Access) BACKGROUND: Specific force, that is the amount of force generated per unit of muscle tissue, is reduced in patients with facioscapulohumeral muscular dystrophy (FSHD). The causes of reduced specific force and its relation with FSHD disease severity are unknown. METHODS: Quantitative muscle magnetic resonance imaging (MRI), measurement of voluntary maximum force generation and quadriceps force-frequency relationship, and vastus lateralis muscle biopsies were performed in 12 genetically confirmed patients with FSHD and 12 controls. RESULTS: Specific force was reduced by ~33% in all FSHD patients independent of disease severity. Quadriceps force-frequency relationship shifted to the right in severe FSHD compared to controls. Fiber type distribution in vastus lateralis muscle biopsies did not differ between groups. CONCLUSIONS: Reduced quadriceps specific force is present in all FSHD patients regardless of disease severity or fatty infiltration. Early myopathic changes, including fibrosis, and non-muscle factors, such as physical fatigue and musculoskeletal pain, may contribute to reduced specific force.

Sarcopenia is a geriatric syndrome that was originally defined as the loss of muscle mass, whereas loss of muscle strength and function come to the forefront in the revised guidelines of sarcopenia (the European Working Group on Sarcopenia in Older People 2, 2018). Accordingly, a decline in muscle quality is increasingly being considered as an important feature in sarcopenia; muscle quality has generally been used to describe the loss of force per cross-sectional area (i.e., specific force). In this chapter, the mechanisms underlying reduced specific force production will be discussed using the data from aged human beings and animals, especially focusing on the intrinsic contractile properties in skeletal muscle fibers. The loss of specific force can be due to decreased Ca2 + release from the sarcoplasmic reticulum, reduced myofibrillar Ca2 + sensitivity, and/or decreased ability of the cross-bridges to generate force.

Study design Basic science study of the relationship between spine pathology and the contractile ability of the surrounding muscles. Objective The aim of this study was to investigate single muscle fiber contractile function in a model of progressive spine mineralization (ENT1-/- mice). Summary of background data Altered muscle structure and function have been associated with various spine pathologies; however, studies to date have provided limited insight into the fundamental ability of spine muscles to actively contract and generate force, and how this may change in response to spine pathology. Methods Experiments were performed on two groups (ENT1-/- [KO] and ENT1+/+ [WT]) of mice at 8 months of age (n = 12 mice/group). Single muscle fibers were isolated from lumbar multifidus and erector spinae, as well as tibialis anterior (a non-spine-related control) and tested to determine their active contractile characteristics. Results The multifidus demonstrated decreases in specific force (type IIax fibers: 36% decrease; type IIb fibers: 29% decrease), active modulus (type IIax: 35% decrease; type IIb: 30% decrease), and unloaded shortening velocity (Vo) (type IIax: 31% decrease) in the ENT1-/- group when compared to WT controls. The erector spinae specific force was reduced in the ENT1-/- mice when compared to WT (type IIax: 29% decrease), but active modulus and Vo were unchanged. There were no differences in any of the active contractile properties of the lower limb TA muscle, validating that impairments observed in the spine muscles were specific to the underlying spine pathology and not the global loss of ENT1. Conclusion These results provide the first direct evidence of cellular level impairments in the active contractile force generating properties of spine muscles in response to chronic spine pathology.Level of Evidence: N/A.

Background Manual palpation is an important part of the clinical examination and generally it has low reliability. The aim of this study was to assess the reliability of a novel method for discriminating 3 different levels of palpation force. Methods This reliability study included 96 healthy physiotherapists and physiotherapy students, who have been taught a new palpation graduated procedure called Visual Ischemic Palpatory Scale (VIPS), aimed to classify the applied pressure based on the finger's ischemia. Force was recorded by a force measurement system putting sensor over a rigid surface. To study the characteristic of VIPS the analysis of variance (ANOVA), Spearman rank correlation coefficient, Intraclass Correlation Coefficient (ICC), Standard Error of Measurements (SEM), and Minimal Detectable Change (MDC) were calculated. Results Three distinct degrees were found with distinct forces expression: 1st degree 76.04 g (95% CI 65.86–86.22), 2nd degree 307.87 g (95% CI 263.29–352.44) and 3rd degree 1319.48 g (CI 1204.73–1434.23). Male participants significantly recorded a greater force than females. Good to excellent reliability across degrees were found (0.89 [95% CI: 0.82–0.97]), and final agreement found that more than 65.6% of sample recorded a force in the cut-offs identified. SEM values became bigger as the recorded force increased and MDC were equal to 48.94 g, 188.73 g, and 379.24 g for 1st, 2nd, and 3rd degree, respectively. Conclusions VIPS would appear to have three distinct degrees, sex dependent, with specific force expression for each degree and a good to excellent intra-rater reliability, but a poor agreement between raters.

Specific force capacities might be a limiting factor for alpine skiing performance, yet there is little consensus on the capabilities in question, and whether they differ between disciplines. We aimed to test discipline (speed and technical) and performance (event-specific world standing) effects on lower limb force-production qualities. National-level skiers (N = 31) performed loaded squat jumps and isometric mid-thigh pulls to detect dynamic force output at extremely low and high velocities and maximum isometric force and rate of force development, respectively. Discipline differences were assessed via a general linear model including performance and allowing for interaction effects, with performance associations further characterized via distinct Pearson's correlations. Jump height did not differentiate disciplines, with absolute power slightly higher in speed athletes (F(1,27) = 4.42, P = .045, ω2 = 0.10), and neither variables were related to performance. Speed athletes possessed greater dynamic force at low velocities (F0 ; F(1,27) = 13.8, P

The work is devoted to an analysis of interference torque of a gas-dynamic bearing gyroscope, while a condition with uniformly changed specific force and carrier angular velocity are taken into account. A five-degrees-of-freedom (5-DOF) model is established considering the translation and tilt of the rotor, which solves dynamic rotor equations and the Reynolds equation simultaneously. The model makes it possible to obtain the rotor trajectory under time-transient specific force and carrier angular velocity. The interference torque of the gyroscope is analyzed based on the rotor trajectory. Results indicate that the gas-dynamic bearings show a significant hysteresis effect with a perturbation of bearing force or bearing moment, which indicates the necessity of transient research. Interference torque is large when the carrier angular velocity starts to change or stops to change, and when the specific force stops to change. When the specific force change rate is less than 8.4 km/s3 with no change of the carrier angular velocity, the condition could be simplified as a steady state, which is consistent with the previous study.

Background Cancer cachexia is a multifactorial wasting syndrome that is characterized by the loss of skeletal muscle mass and weakness, which compromises physical function, reduces quality of life, and ultimately can lead to mortality. Experimental models of cancer cachexia have recapitulated this skeletal muscle atrophy and consequent decline in muscle force‐generating capacity. We address these issues in a novel transgenic mouse model Kras, Trp53, and Pdx‐1‐Cre (KPC) of pancreatic ductal adenocarcinoma using multi‐parametric magnetic resonance measures. Methods KPC mice (n = 10) were divided equally into two groups (n = 5 per group) depending on the size of the tumour, that is, tumour size 250 mm3. Using multi‐parametric magnetic resonance measures, we demonstrated the changes in the gastrocnemius muscle at the microstructural level. In addition, we evaluated skeletal muscle contractile function in KPC mice using an in vivo approach. Results Increase in tumour size resulted in decrease in gastrocnemius maximum cross‐sectional area, decrease in T2 relaxation time, increase in magnetization transfer ratio, decrease in mean diffusivity, and decrease in radial diffusivity of water across the muscle fibres. Finally, we detected significant decrease in absolute and specific force production of gastrocnemius muscle with increase in tumour size. Conclusions Our findings indicate that increase in tumour size may cause alterations in structural and functional parameters of skeletal muscles and that MR parameters may be used as sensitive biomarkers to non‐invasively detect structural changes in cachectic muscles.

Gene therapy approaches for DMD using recombinant adeno-associated viral (rAAV) vectors to deliver miniaturized (or micro) dystrophin genes to striated muscles have shown significant progress. However, concerns remain about the potential for immune responses against dystrophin in some patients. Utrophin, a developmental paralogue of dystrophin, may provide a viable treatment option. Here we examine the functional capacity of an rAAV-mediated microutrophin (μUtrn) therapy in the mdx4cv mouse model of DMD. We found that rAAV-μUtrn led to improvement in dystrophic histopathology & mostly restored the architecture of the neuromuscular and myotendinous junctions. Physiological studies of tibialis anterior muscles indicated peak force maintenance, with partial improvement of specific force. A fundamental question for μUtrn therapeutics is not only can it replace critical functions of dystrophin, but whether full-length utrophin impacts the therapeutic efficacy of the smaller, highly expressed μUtrn. As such, we found that μUtrn significantly reduced the spacing of the costameric lattice relative to full-length utrophin. Further, immunostaining suggested the improvement in dystrophic pathophysiology was largely influenced by favored correction of fast 2b fibers. However, unlike μUtrn, μdystrophin (μDys) expression did not show this fiber type preference. Interestingly, μUtrn was better able to protect 2a and 2d fibers in mdx:utrn-/- mice than in mdx4cv mice where the endogenous full-length utrophin was most prevalent. Altogether, these data are consistent with the role of steric hindrance between full-length utrophin & μUtrn within the sarcolemma. Understanding the stoichiometry of this effect may be important for predicting clinical efficacy., Author summary Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by mutations in the dystrophin gene. Utrophin is structurally similar to dystrophin and can potentially be utilized to prevent muscle necrosis in preclinical models of DMD. Consequently, utrophin-mediated therapies are a primary target for treating DMD, particularly as it may circumvent immune responses to dystrophin-mediated therapies. One promising therapeutic option is to utilize recombinant adeno-associated viral vectors (rAAV) to deliver a rationally designed miniaturized utrophin (μUtrn) to striated muscles to prevent necrosis. Here, we found that rAAV-μUtrn can profoundly prevent skeletal muscle necrosis in the mdx4cv mouse model of DMD. μUtrn was also able to replace many functions of dystrophin at the neuromuscular synapse and myotendinous junctions. However, we provide several lines of in vivo evidence that steric hindrance between μUtrn and the endogenous full-length utrophin on the sarcolemma impacts the longevity of the therapy in a muscle fiber-type selective manner. Understanding the stoichiometry of this effect may be important for predicting clinical efficacy.

Androgen deprivation therapy (ADT) decreases muscle mass, force, and physical activity levels, but it is unclear whether disuse atrophy and testosterone suppression are additive. Additionally, conflicting reports exist on load-mediated hypertrophy during ADT and if protein supplementation offsets these deficits. This study sought to determine the role of testosterone suppression and a high-protein diet on 1) immobilization-induced atrophy and 2) muscle regrowth during reloading. Eight-week-old male Fischer 344 rats underwent sham surgery (Sham), castration surgery (ORX), or ORX and a high-casein diet supplemented with branched-chain amino acids (BCAA) (ORX+CAS/AA) followed by 10 days of unilateral immobilization (IMM) and 0, 6, or 14 days of reloading. With IMM, body mass gains were ~8% greater than ORX and ORX+CAS/AA that increased to 15% during reloading (both P < 0.01). IMM reduced muscle mass by 11-34% (all P < 0.01) and extensor digitorum longus and soleus (SOL) force by 21% and 49% (both P < 0.01), respectively, with no group differences. During reloading, castration reduced gastrocnemius mass (~12%) at 6 days and SOL mass (~20%) and SOL force recovery (~46%) at 14 days relative to Sham (all P < 0.05). Specific force reduced castration deficits, indicating that muscle atrophy was a key contributor. IMM decreased SOL cross-sectional area by 30.3% (P < 0.001), with a trend for reduced regrowth in ORX and ORX+CAS/AA following reloading (P = 0.083). Castration did not exacerbate disuse atrophy but may impair recovery of muscle function, with no benefit from a CAS/AA diet during reloading. Examining functional outcomes in addition to muscle mass during dietary interventions provides novel insights into muscle regrowth during ADT.NEW & NOTEWORTHY Low testosterone levels during skeletal muscle disuse did not worsen declines in muscle mass and function, although hypogonadism may attenuate recovery during subsequent reloading. Diets high in casein did not improve outcomes during immobilization or reloading. Practical strategies are needed that do not compromise caloric intake yet provide effective protein doses to augment these adverse effects.

The need for accurate and efficient force fields for modeling 3D structures of macrobiomolecules and in particular intrinsically disordered proteins (IDPs) has increased with recent findings to associate IDPs and human diseases. However, most conventional protein force fields and recent IDP-specific force fields are limited in reproducing accurate structural features of IDPs. Here, we present an environmental specific precise force field (ESFF1) based on CMAP corrections of 71 different sequence environments to improve the accuracy and efficiency of MD simulation for both IDPs and folded proteins. MD simulations of 84 different short peptides, IDPs, and structured proteins show that ESFF1 can accurately reproduce spectroscopic properties for different peptides and proteins whether they are disordered or ordered. The successful ab initio folding of five fast-folding proteins further supports the reliability of ESFF1. The extensive analysis documented here shows that ESFF1 is able to achieve a reasonable balance between ordered and disordered states in protein simulations.

Background. Both fasting and ageing processes lead to muscle wasting. We studied the effect of single 48 h fasting on soleus skeletal muscle mass and force in young and old mice.Methods. The study involved 18 young and 13 old mice. Body and soleus (SOL) muscle mass were measured followed by assessment of peak and specific SOL force under ex vivo conditions. SOL muscle half-relaxation time and 20 Hz to 100 Hz force ratio were also measured.Results. After fasting, weight loss was greater (p < .05) in young mice compared to old mice (17.0 ± 2.6 versus 12.0 ± 1.7%, respectively). Fasted young, but not old mice showed reduction (p < .05) in SOL mass compared to the control values. On the other hand, specific SOL force was reduced (p < .05) only in old mice, while 20 Hz to 100 Hz force ratio decreased (p < .05) only in young mice after fasting.Conclusions. Our results showed that 48 h fasting caused lower SOL muscle peak and specific force in old but not young mice. Keywords: starvation, peak force, specific force, ageing.

Muscle synergies are defined as the specific co-activation of muscle groups to accomplish function level targets. The hypothesis of muscle synergies helps simplify the motor coordination problem by decreasing the numbers of central nervous system signals. The purpose of this research was to discuss how muscle coordination works across different individuals during the performance of a cyclic movement at specific force levels. We acquired Electromyography (EMG) signals from seven right upper-limb muscles of four participants as they operated the hand-cycle ergometer. Non-negative matrix factorization (NNMF) was used to extract muscle synergies from the EMG signals and compared across the participants at a specific power level. We found that five synergies were shared across participants. Also, the recruitment profile for those synergies appeared to be similar with only slight deviations. Therefore, we conclude that during a constrained rotational motion at constant speed (50 r.p.m) and constant power level (20 watts), the muscle synergies were preserved across participants. The results of this study would be useful in designing assistive devices for rehabilitation purposes.

ObjectiveTo investigate single muscle fiber contractile performance in muscle biopsies from patients with facioscapulohumeral muscular dystrophy (FSHD), one of the most common hereditary muscle disorders.MethodsWe collected 50 muscle biopsies (26 vastus lateralis, 24 tibialis anterior) from 14 patients with genetically confirmed FSHD and 12 healthy controls. Single muscle fibers (n = 547) were isolated for contractile measurements. Titin content and titin phosphorylation were examined in vastus lateralis muscle biopsies.ResultsSingle muscle fiber specific force was intact at saturating and physiologic calcium concentrations in all FSHD biopsies, with (FSHDFAT) and without (FSHDNORMAL) fatty infiltration, compared to healthy controls. Myofilament calcium sensitivity of force is increased in single muscle fibers obtained from FSHD muscle biopsies with increased fatty infiltration, but not in FSHD muscle biopsies without fatty infiltration (pCa50: 5.77–5.80 in healthy controls, 5.74–5.83 in FSHDNORMAL, and 5.86–5.90 in FSHDFAT single muscle fibers). Cross-bridge cycling kinetics at saturating calcium concentrations and myofilament cooperativity did not differ from healthy controls. Development of single muscle fiber passive tension was changed in all FSHD vastus lateralis and in FSHDFAT tibialis anterior, resulting in increased fiber stiffness. Titin content was increased in FSHD vastus lateralis biopsies; however, titin phosphorylation did not differ from healthy controls.ConclusionMuscle weakness in patients with FSHD is not caused by reduced specific force of individual muscle fibers, even in severely affected tissue with marked fatty infiltration of muscle tissue.

Cancer cachexia is the loss of lean muscle mass with or without loss of fat mass that is often highlighted by a progressive loss of skeletal muscle mass and function. The mechanisms behind the cachexia‐related loss of skeletal muscle are poorly understood, including cachexia‐related muscle functional impairments. Existing models have revealed some potential mechanisms, but appear limited to how the cancer develops and the type of tumors that form. We studied the C57BL6/J (B6) ApcMin/+ Tg::Fabp1‐Cre TG::PIK3ca* (CANCER) mouse. In this model, mice develop highly aggressive intestinal cancers. We tested whether CANCER mice develop cancer cachexia, if muscle function is altered and if sex differences are present. Both female and male mice, B6 (CONTROL) and CANCER mice, were analyzed to determine body weight, hindlimb muscle mass, protein concentration, specific force, and fatigability. Female CANCER mice had reduced body weight and hindlimb muscle mass compared with female CONTROL mice, but lacked changes in protein concentration and specific force. Male CANCER mice had reduced protein concentration and reduced specific force, but lacked altered body weight and muscle mass. There were no changes in fatigability in either group. Our study demonstrates that CANCER mice present an early stage of cachexia, have reduced specific force in male CANCER mice and develop a sex‐dependent cachexia phenotype. However, CANCER mice lack certain aspects of the syndrome seen in the human scenario and, therefore, using the CANCER mice as a preclinical model does not seem sufficient in order to maximize the translation of preclinical findings to humans., The mechanisms behind the progressive loss of skeletal muscle mass and function seen in patients with cancer cachexia are still largely unknown, thus we tested whether a new murine model of colorectal cancer could better represent the human condition. We concluded that although the tumor‐bearing model tested had reductions in body weight, muscle mass, specific force and a sex‐specific phenotype, the model tested had a limited lifespan and ultimately impaired the ability to translate findings to the human condition.

The ratio between muscle strength and muscle cross-sectional area is called the specific force. Fatty replacement of muscles is seen in many myopathies, affecting the specific force, without necessarily affecting the ability of the remaining muscle fibers to contract. This ability is called the contractility and is the ratio between muscle strength and the lean muscle cross-sectional area, i.e. the contractile cross-sectional area. We hypothesized that contractility is disrupted in patients with congenital myopathy, because of defects in contractile proteins of the sarcomere. Peak torque across ankle and knee joints was measured by isokinetic dynamometry in 16 patients with congenital myopathy and 13 healthy controls. Five patients only participated partially in the dynamometer measurements due to severe muscle weakness. Dixon MRI technique was used to quantify muscle fat fractions and calculate cross-sectional area. Patients with congenital myopathy had lower cross-sectional area in all muscle groups (P0.01), higher fat fraction (P0.01) and less strength (P0.005) in all studied muscle groups. Their fat content was more than doubled and peak torque lower than half that in healthy controls. Muscle contractility was reduced (P0.01) in three of four patient muscle groups. In conclusion, muscle contractility was reduced in patients with congenital myopathy, across different diagnoses, and was independent of the level of muscle fat fraction, suggesting that intrinsic defects of the myocyte are responsible for reduced contractility.

SummaryThe motor control resolution of any animal behavior is limited to the minimal force step available when activating muscles, which is set by the number and size distribution of motor units (MUs) and muscle specific force [1, 2]. Birdsong is an excellent model system for understanding sequence learning of complex fine motor skills [3], but we know surprisingly little how the motor pool controlling the syrinx is organized [4] and how MU recruitment drives changes in vocal output [5]. Here we combine measurements of syringeal muscle innervation ratios with muscle stress and an in vitro syrinx preparation to estimate MU size distribution and the control resolution of fundamental frequency (fo), a key vocal parameter, in zebra finches. We show that syringeal muscles have extremely small MUs, with 50% innervating ≤ 3, and 13 – 17% innervating a single muscle fiber. Combined with the lowest specific stress (5 mN/mm2) known to skeletal vertebrate muscle, small force steps by the major fo controlling muscle provide control of 50 mHz to 4.2 Hz steps per MU. We show that the song system has the highest motor control resolution possible in the vertebrate nervous system and suggest this evolved due to strong selection on fine gradation of vocal output. Furthermore, we propose that high-resolution motor control was a key feature contributing to the radiation of songbirds that allowed diversification of song and speciation by vocal space expansion.

Осуществлено исследование силовых характеристик операции высокоскоростного холодного радиального обжатия трубной заготовки на оправке, обосновывающее возможность реализации операции в перспективной технологии изготовления труб из конструкционной легированной стали, функционирующих в условиях высоких импульсных термодинамических нагрузок, с привлечением инженерного метода расчета.

NEW FINDINGS What is the central question of the study? What are the consequences of reducing circulating sphingosine-1-phosphate (S1P) for muscle physiology in the murine model of Duchenne muscular dystrophy (DMD)? What is the main result and its importance? Reduction of the circulating S1P level in mdx mice aggravates the dystrophic phenotype, as seen by an increase in fibre atrophy, fibrosis and loss of specific force, suggesting that S1P signalling is a potential therapeutic target in DMD. Although further studies are needed, plasma S1P levels have the intriguing possibility of being used as a biomarker for disease severity, an important issue in DMD. ABSTRACT Sphingosine-1-phosphate (S1P) is an important regulator of skeletal muscle properties. The dystrophin-deficient mdx mouse possesses low levels of S1P (∼50%) compared with wild type. Increased S1P availability was demonstrated to ameliorate the dystrophic phenotype in Drosophila and in mdx mice. Here, we analysed the effects produced by further reduction of S1P availability on the mass, force and regenerative capacity of dystrophic mdx soleus. Circulating S1P was neutralized by a specific anti-S1P antibody (S1P-Ab) known to lower the extracellular concentration of this signalling lipid. The S1P-Ab was administered intraperitoneally in adult mdx mice every 2 days for the duration of experiments. Soleus muscle properties were analysed 7 or 14 days after the first injection. The decreased availability of circulating S1P after the 14 day treatment reduced mdx soleus fibre cross-sectional area (-16%, P