Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure.

In striated muscle, the sarcomeric protein myosin-binding protein-C (MyBP-C) is bound to the myosin thick filament and is predicted to stabilize myosin heads in a docked position against the thick filament, which limits crossbridge formation. Here, we use the homozygous Mybpc2 knockout (C2-/-) mouse line to remove the fast-isoform MyBP-C from fast skeletal muscle and then conduct mechanical functional studies in parallel with small-angle X-ray diffraction to evaluate the myofilament structure. We report that C2-/- fibers present deficits in force production and calcium sensitivity. Structurally, passive C2-/- fibers present altered sarcomere length-independent and -dependent regulation of myosin head conformations, with a shift of myosin heads towards actin. At shorter sarcomere lengths, the thin filament is axially extended in C2-/-, which we hypothesize is due to increased numbers of low-level crossbridges. These findings provide testable mechanisms to explain the etiology of debilitating diseases associated with MyBP-C.

Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure.

In striated muscle, some sarcomere proteins regulate crossbridge cycling by varying the propensity of myosin heads to interact with actin. Myosin-binding protein C (MyBP-C) is bound to the myosin thick filament and is predicted to interact and stabilize myosin heads in a docked position against the thick filament and limit crossbridge formation, the so-called OFF state. Via an unknown mechanism, MyBP-C is thought to release heads into the so-called ON state, where they are more likely to form crossbridges. To study this proposed mechanism, we used the C2-/- mouse line to knock down fast-isoform MyBP-C completely and total MyBP-C by ~24%, and conducted mechanical functional studies in parallel with small-angle X-ray diffraction to evaluate the myofilament structure. We report that C2-/- fibers presented deficits in force production and reduced calcium sensitivity. Structurally, passive C2-/- fibers presented altered SL-independent and SL-dependent regulation of myosin head ON/OFF states, with a shift of myosin heads towards the ON state. Unexpectedly, at shorter sarcomere lengths, the thin filament was axially extended in C2-/- vs. non-transgenic controls, which we postulate is due to increased low-level crossbridge formation arising from relatively more ON myosins in the passive muscle that elongates the thin filament. The downstream effect of increasing crossbridge formation in a passive muscle on contraction performance is not known. Such widespread structural changes to sarcomere proteins provide testable mechanisms to explain the etiology of debilitating MyBP-C-associated diseases.

The history-dependent features of muscle force production: A challenge to the cross-bridge theory and their functional implications.

The cross-bridge theory predicts that muscle force is determined by muscle length and the velocity of active muscle length changes. However, before the formulation of the cross-bridge theory, it had been observed that the isometric force at a given muscle length is enhanced or depressed depending on active muscle length changes before that given length is reached. These enhanced and depressed force states are termed residual force enhancement (rFE) and residual force depression (rFD), respectively, and together they are known as the history-dependent features of muscle force production. In this review, we introduce early attempts in explaining rFE and rFD before we discuss more recent research from the past 25 years which has contributed to a better understanding of the mechanisms underpinning rFE and rFD. Specifically, we discuss the increasing number of findings on rFE and rFD which challenge the cross-bridge theory and propose that the elastic element titin plays a role in explaining muscle history-dependence. Accordingly, new three-filament models of force production including titin seem to provide better insight into the mechanism of muscle contraction. Complementary to the mechanisms behind muscle history-dependence, we also show various implications for muscle history-dependence on in-vivo human muscle function such as during stretch-shortening cycles. We conclude that titin function needs to be better understood if a new three-filament muscle model which includes titin, is to be established. From an applied perspective, it remains to be elucidated how muscle history-dependence affects locomotion and motor control, and whether history-dependent features can be changed by training.

Characterizing residual and passive force enhancements in cardiac myofibrils.

Residual force enhancement (RFE), an increase in isometric force after active stretching of a muscle compared with the purely isometric force at the corresponding length, has been consistently observed throughout the structural hierarchy of skeletal muscle. Similar to RFE, passive force enhancement (PFE) is also observable in skeletal muscle and is defined as an increase in passive force when a muscle is deactivated after it has been actively stretched compared with the passive force following deactivation of a purely isometric contraction. These history-dependent properties have been investigated abundantly in skeletal muscle, but their presence in cardiac muscle remains unresolved and controversial. The purpose of this study was to investigate whether RFE and PFE exist in cardiac myofibrils and whether the magnitudes of RFE and PFE increase with increasing stretch magnitudes. Cardiac myofibrils were prepared from the left ventricles of New Zealand White rabbits, and the history-dependent properties were tested at three different final average sarcomere lengths (n = 8 for each), 1.8, 2, and 2.2 µm, while the stretch magnitude was kept at 0.2 µm/sarcomere. The same experiment was repeated with a final average sarcomere length of 2.2 µm and a stretching magnitude of 0.4 µm/sarcomere (n = 8). All 32 cardiac myofibrils exhibited increased forces after active stretching compared with the corresponding purely isometric reference conditions (p < 0.05). Furthermore, the magnitude of RFE was greater when myofibrils were stretched by 0.4 compared with 0.2 µm/sarcomere (p < 0.05). We conclude that, like in skeletal muscle, RFE and PFE are properties of cardiac myofibrils and are dependent on stretch magnitude.

The Nonintuitive Contributions of Individual Quadriceps Muscles to Patellar Tracking.

The purpose of this study was to quantify the contribution of the individual quadriceps muscles to patellar tracking. The individual and/or combined quadriceps muscles were activated in rabbits (n = 6) during computer-controlled flexion/extension of the knee. Three-dimensional patellar tracking was measured for the vastus lateralis, vastus medialis, and rectus femoris when activated alone and when activated simultaneously at different frequencies, producing a range of knee extensor torques. Patellar tracking changed substantially as a function of knee extensor torque and differed between muscles. Specifically, when all quadriceps muscles were activated simultaneously, the patella shifted more medially and proximally and rotated and tilted more medially compared with when vastus lateralis and rectus femoris were activated alone (P < .05), whereas vastus medialis activation alone produced a similar tracking pattern to that observed when all quadriceps muscles were activated simultaneously. Furthermore, patellar tracking for a given muscle condition shifted more medially and proximally and rotated and tilted more medially with increasing knee extensor torques across the entire range of knee joint angles. The authors conclude that patellar tracking depends crucially on knee extensor force/torque and that vastus medialis affects patellar tracking in a distinctly different way than vastus lateralis and rectus femoris, which produce similar tracking patterns.

Gender disparities in fear of failure among 15-year-old students: The role of gender inequality, the organisation of schooling and economic conditions.

INTRODUCTION: Prior research indicates that female students express higher fear of failure than male students and that fear of failure is associated with lower social and emotional well-being and higher levels of stress, anxiety, burnout and depression. Fear of failure also leads individuals to limit their choices and take fewer risks than would be warranted given their ability and context to minimise the possibility of failing. METHODS: We examined cross-country differences in gender gaps in fear of failure as well as factors that explain gender gaps and variations of gender gaps across countries using multilevel modelling techniques. Participants were 517,047 15-year-old students from 59 countries who took part in the 2018 Programme for International Student Assessment (PISA). RESULTS: Within countries, students with higher reading achievement and who lacked a growth mindset reported higher fear of failure. The gender gap in fear of failure was especially high among high-achieving students and students with high-achieving peers. The size of the gender gap in fear of failure differed across countries: it was higher in countries with higher levels of economic prosperity, with lower levels of societal-level gender inequality and countries with comprehensive education systems. CONCLUSIONS: The greater prevalence of fear of failure among female students among high-achieving students attending high-achieving schools in prosperous and more gender equal societies could help to explain the paradox of the persistent underrepresentation of females in certain occupations in contexts that are most supportive of females.

Effect of Vastus Medialis Loss on Rabbit Patellofemoral Joint Contact Pressure Distribution.

Vastus medialis (VM) weakness is thought to alter patellar tracking, thereby changing the loading of the patellofemoral joint (PFJ), resulting in patellofemoral pain. However, it is challenging to measure VM force and weakness in human studies, nor is it possible to measure the associated mechanical changes in the PFJ. To obtain fundamental insight into VM weakness and its effects on PFJ mechanics, the authors determined PFJ loading in the presence of experimentally simulated VM weakness. Skeletally mature New Zealand White rabbits were used (n = 6), and the vastus lateralis, VM, and rectus femoris were stimulated individually through 3 custom-built nerve cuff electrodes. Muscle torque and PFJ pressure distribution were measured while activating all muscles simultaneously, or when the vastus lateralis and rectus femoris were activated, while VM was not, to simulate a quadriceps muscle strength imbalance. For a given muscular joint torque, peak pressures were greater and joint contact areas were smaller when simulating VM weakness compared with the condition where all muscles were activated simultaneously. The results in the rabbit model support that VM weakness results in altered PFJ loading, which may cause patellofemoral pain, often associated with a strength imbalance of the knee extensor muscle group.

Residual and passive force enhancement in skinned cardiac fibre bundles.

In skeletal muscle, steady-state force is consistently greater following active stretch than during a purely isometric contraction at the same length (residual force enhancement; RFE). Similarly, when deactivated, the force remains higher following active stretch than following an isometric condition (passive force enhancement; PFE). RFE and PFE have been associated with the sarcomere protein titin, but skeletal and cardiac titin have different structures, and results regarding RFE in cardiac muscle have been inconsistent and contradictory. Therefore, the purpose of this study was to determine if cardiac muscle exhibits RFE and PFE. Skinned fibre bundles (n = 10) were activated isometrically at a sarcomere length of 2.2 µm and actively stretched by 15% of their length. The resultant active and passive forces were compared to the corresponding forces obtained for purely isometric contractions at the long length. RFE was observed in all fibre bundles, averaging 5.5 ± 2.5% (ranging from 2.3 to 9.4%). PFE was observed in nine of the ten bundles, averaging 11.1 ± 6.5% (ranging from -2.1 to 18.7%). Stiffness was not different between the active isometric and the force enhanced conditions, but was higher following deactivation from the force-enhanced compared to the isometric reference state. We conclude that there is RFE and PFE in cardiac muscle. We speculate that cardiac muscle has the same RFE capability as skeletal muscle, and that the most likely mechanism for the RFE and PFE is the engagement of a passive structural element during active stretching.

Why do muscles lose torque potential when activated within their agonistic group?

Agonistic muscles lose approximately 20% of their individual torque-generating capacity when activated with their agonistic muscles compared with when stimulated in isolation. In this study, we (1) tested if this loss in torque was accompanied by a corresponding loss in force, thereby testing the potential role of changes in moment arms between conditions; (2) removed all inter-muscular connections between the quadriceps muscles, thus determining the potential role of inter-muscular force transmission; and (3) systematically changed the inter-muscular pressure by performing experiments at different activation/force levels, thereby exploring the possible role of inter-muscular pressure in the loss of torque capacity with simultaneous muscle activation. Experiments were performed in a New Zealand white rabbit quadriceps model (N=5). Torque and force were measured during activation of femoral nerve branches that supply the individual quadriceps muscles while activating these branches simultaneously and in isolation. Regardless of joint angle and inter-muscular connections between muscles, the differences in torque values between the simultaneous and the isolated activation of the quadriceps muscles were also observed for the directly measured force values. Mean differences in simultaneous and isolated muscle activation remained similar between the intact and separated conditions: torque difference 21±5% of maximum isometric torque of intact condition (MICtorque), versus 19±6% MICtorque, respectively, and force difference 18±3% MICforce versus 19±7% MICforce, respectively. The absolute torque loss was independent of the force, and thus presumably the inter-muscular pressures. Based on these results, we conclude that the torque deficit observed during simultaneous compared with isolated muscle activation is not primarily caused by moment arm, inter-muscular pressure or inter-muscular force transmission. The mechanisms underlying loss of force capacity during agonistic muscle contraction remain unknown.

Contribution of individual quadriceps muscles to knee joint mechanics.

Many attempts have been made to determine the contribution of individual muscles in an agonistic group to the mechanics of joints. However, previous approaches had the limitations that muscles often could not be controlled in a precise manner, that individual muscles in an agonistic group could not be activated individually, and that individual muscle contributions could not be measured in an actively contracting agonistic group. Here, we introduce a surgical approach that allows for controlled activation of individual muscles of an agonistic group. The approach is illustrated for the vastus lateralis (VL), vastus medialis (VM) and rectus femoris (RF) of the rabbit quadriceps femoris group. We provide exemplar results for potential applications of the approach, such as measuring the pressure distribution in the patellofemoral joint, and the torque-angle relationship of VL, VM and RF when activated individually and when the three muscles are activated simultaneously.

The mechanics of agonistic muscles.

INTRODUCTION: In this study, we tested two assumptions that have been made in experimental studies on muscle mechanics: (i) that the torque-angle properties are similar among agonistic muscles crossing a joint, and (ii) that the sum of the torque capacity of individual muscles adds up to the torque capacity of the agonist group. METHODS: Maximum isometric torque measurements were made using a specifically designed animal knee extension dynamometer for the intact rabbit quadriceps muscles (n = 10) for knee angles between 60 and 120°. The nerve branches of the vastus lateralis (VL), vastus medialis (VM) and rectus femoris (RF) muscles were carefully dissected, and a custom made nerve cuff electrode was implanted on each branch. Knee extensor torques were measured for four maximal activation conditions at each knee angle: VL activation, VM activation, RF activation, and activation of all three muscles together. RESULTS: With the exception of VL, the torque-angle relationships of the individual muscles did not have the shape of the torque-angle relationship obtained when all muscles were activated simultaneously. Furthermore, the maximum torque capacity obtained by adding the individual torque capacities of VL, VM and RF was approximately 20% higher than the torques produced when the three muscles were activated simultaneously. DISCUSSION: These results bring into question our understanding of in-vivo muscle contraction and challenge assumptions that are sometimes made in human and animal muscle force analyses.

Asynchronous Alterations of Muscle Force and Tendon Stiffness Following 8 Weeks of Resistance Exercise with Whole-Body Vibration in Older Women.

This study aimed to examine whether muscle force and tendon stiffness in a muscle-tendon complex alter synchronously following 8-week whole-body vibration (WBV) training in older people. Forty older women aged 65 years and older were randomly assigned into control (CON, n = 15) and whole-body vibration (WBV) training groups (exposure time, n = 13; vibration intensity, n = 12). For the training groups, a 4-week detraining period was completed following the training period. Throughout the training/detraining period, force of the medial gastrocnemius (MG) muscle and stiffness of the Achilles tendon were assessed four times (0, 4, 8, and 12 weeks) using a combined system of dynamometer and ultrasonography. While muscle force gradually increased throughout the training period (p < .05), a significant increase in tendon stiffness was observed after 8 weeks (p < .05). These findings indicated that, during the early phase of WBV training, muscle force and tendon stiffness changed asynchronously, which might be a factor in possible musculotendinous injuries.

Predictors of quality of life in ulcerative colitis: the importance of symptoms and illness representations.

BACKGROUND: Establishing predictors of quality of life (QoL) in individuals with inflammatory bowel disease could help to identify those patients who are most likely to experience poor QoL and to target therapeutic interventions appropriately. We aimed to investigate how disease-specific QoL depends on demographic, diseaserelated, and physiological markers of disease activity, cognitive representations of illness, and perceived general health status. METHODS: A total of 111 individuals completed the Inflammatory Bowel Disease Questionnaire (IBDQ), the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and the Illness Perception Questionnaire (IPQ). The extent of disease was determined from records, and disease activity was determined by a symptom index. Bivariate analyses and multivariate regression models were used to identify predictors of disease-specific QoL. RESULTS: Bivariate analyses showed that symptom-related disease activity, elements of illness representation measured by the IPQ, and elements of physical and mental health measured by the SF-36 were the only variables that were strongly or moderately correlated with disease-specific QoL. Multivariate regression modeling showed that disease activity was the major explanatory variable for each of the 4 domains and for the total score on the IBDQ. CONCLUSION: This study highlights the strong relationship between individuals' symptoms and all domains of their health-related QoL, but shows little association with age, gender, physiological markers of disease activity, or anatomic disease extent. Perceptions of the condition were relatively weak predictors of self-reported QoL. The best strategy for improving QoL among individuals with ulcerative colitis may be to find ways to reduce their symptoms.