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Heart failure with preserved ejection fraction (HFpEF) and right ventricular (RV) dysfunction are frequent complications of diabetic cardiomyopathy. Here we aimed to characterize RV and left ventricular (LV) remodeling and its prevention by vardenafil (a long-acting phosphodiesterase-5A (PDE-5A) inhibitor) administration in a diabetic HFpEF model. Zucker Diabetic Fatty (ZDF) and control, ZDF Lean (Lean) male rats received 10 mg/kg vardenafil (ZDF + Vard; Lean + Vard) per os, on a daily basis for a period of 25 weeks. In vitro force measurements, biochemical and histochemical assays were employed to assess cardiomyocyte function and signaling. Vardenafil treatment increased cyclic guanosine monophosphate (cGMP) levels and decreased 3-nitrotyrosine (3-NT) levels in the left and right ventricles of ZDF animals, but not in Lean animals. Cardiomyocyte passive tension (Fpassive) was higher in LV and RV cardiomyocytes of ZDF rats than in those receiving preventive vardenafil treatment. Levels of overall titin phosphorylation did not differ in the four experimental groups. Maximal Ca2+-activated force (Fmax) of LV and RV cardiomyocytes were preserved in ZDF animals. Ca2+-sensitivity of isometric force production (pCa50) was significantly higher in LV (but not in RV) cardiomyocytes of ZDF rats than in their counterparts in the Lean or Lean + Vard groups. In accordance, the phosphorylation levels of cardiac troponin I (cTnI) and myosin binding protein-C (cMyBP-C) were lower in LV (but not in RV) cardiomyocytes of ZDF animals than in their counterparts of the Lean or Lean + Vard groups. Vardenafil treatment normalized pCa50 values in LV cardiomyocytes, and it decreased pCa50 below control levels in RV cardiomyocytes in the ZDF + Vard group. Our data illustrate partially overlapping myofilament protein alterations for LV and RV cardiomyocytes in diabetic rat hearts upon long-term PDE-5A inhibition. While uniform patterns in cGMP, 3-NT and Fpassive levels predict identical effects of vardenafil therapy for the diastolic function in both ventricles, the uneven cTnI, cMyBP-C phosphorylation levels and pCa50 values implicate different responses for the systolic function.

Warm-up is a fundamental preparatory phase for optimizing performance, yet its acute effects may depend on the specificity of the protocol to the target task. This pilot study compared a General, mobility-based Warm-Up (GWU) with a low-intensity, bodyweight Movement-Specific Warm-Up (MSWU) replicating squat biomechanics on maximal isometric force and neuromuscular activation during isometric squat. Eight resistance-trained men (age 23.5 ± 1.2 years; height 182.9 ± 5.9 cm; body mass 84.3 ± 9.1 kg; 1RM back squat 146 ± 19 kg) completed two randomized, counterbalanced sessions. Each session included a standardized preliminary warm-up, baseline maximal isometric high-bar back squat at 90° knee flexion, and either the GWU or the MSWU, followed by a 2-min rest and reassessment. Peak force and surface EMG of vastus medialis (VM), vastus lateralis (VL), rectus femoris (RF), gluteus maximus (GMax), and biceps femoris (BF) were measured. Completion time did not differ between protocols (~6–7 min; p = 0.806). Peak force significantly decreased after the GWU (−3.8%; p = 0.004; d = 1.47) but was maintained following the MSWU (−1.9%; p = 0.138; d = 0.59). Between-protocol differences in peak force were not significant (p = 0.186; d = 0.52). No significant changes were observed in normalized GMax activity or total integrated EMG. These results indicate that, for isometric, task-specific performance, a brief movement-specific warm-up better preserves force-generating capacity than a general mobility routine of similar duration, emphasizing the importance of biomechanical specificity in warm-up design.

This study aimed to evaluate whether combining force–velocity Fv and force-position Fp models, originally developed for single-joint movements, could effectively characterize force production during the push-off phase of a vertical jump. Six force–velocity-position Fv,p models, integrating three Fv (Anderson, Hill, and Linear) and two Fp (Cosine and Quadratic) models were assessed. Fifteen trained CrossFit athletes performed maximal countermovement jumps under varying loads and push-off depths with ground reaction forces recorded via force plates. All six models demonstrated high goodness-of-fit, with r2 ranging from 0.885 to 0.886 and RMSE values ranging from 262.6 to 266.5 N, effectively capturing key experimental data characteristics. No significant differences in fitting or descriptive capacity were observed among Anderson, Hill, and Linear models, reflecting the near-linear behavior of the force–velocity relationships in vertical jump. Nevertheless, the Linear model offers simplicity and interpretability by focusing on key physiological parameters (e.g., maximal force, maximal velocity, and optimal position) commonly used in applied sports contexts. The Cosine and Quadratic models showed no significant impact on overall fit quality, although significant differences in optimal vertical position (popt) and theoretical maximal force (Fmax) were observed. When paired with the Linear model, the Quadratic model slightly reduced Fmax deviations in participants with slightly curvilinear force–velocity relationships. This study highlights the strength of a simple three-parameter heuristic model, whose parameters are biomechanically and physiologically relevant, in describing the force production as a function of position and velocity. This combination of simplicity and interpretability represents a significant step forward in the modeling of multi-joint movements, offering practical insights for sport performance optimization.

We explored two types of anticipatory synergy adjustments (ASA) during accurate four-finger total force production task. The first type is a change in the index of force-stabilizing synergy during a steady state when a person is expecting a signal to produce a quick force change, which is seen even when the signal does not come (steady-state ASA). The other type is the drop in in the synergy index prior to a planned force change starting at a known time (transient ASA). The subjects performed a task of steady force production at 10% of maximal voluntary contraction (MVC) followed by a ramp to 20% MVC over 1 s, 3 s, and as a step function (0 s). In another task, in 50% of the trials during the steady-state phase, an unexpected signal could come requiring a quick force pulse to 20% MVC (0-surprise). Inter-trial variance in the finger force space was used to quantify the index of force-stabilizing synergy within the uncontrolled manifold hypothesis. We observed significantly lower synergy index values during the steady state in the 0-ramp trials compared to the 1-ramp and 3-ramp trials. There was also larger transient ASA during the 0-ramp trials. In the 0-surprise condition, the synergy index was significantly higher compared to the 0-ramp condition whereas the transient ASA was significantly larger. The finding of transient ASA scaling is of importance for clinical studies, which commonly involve populations with slower actions, which can by itself be associated with smaller ASAs. The participants varied the sharing pattern of total force across the fingers more in the task with “surprises”. This was coupled to more attention to precision of performance, i.e., inter-trial deviations from the target as reflected in smaller variance affecting total force, possibly reflecting higher concentration on the task, which the participants perceived as more challenging compared to a similar task without surprise targets.

Accurate control of force on the environment is mechanically necessary for many tasks involving the lower extremities. We investigated drifts in the horizontal (shear) active force produced by right-footed seated subjects and the effects of force matching by the other foot. Subjects generated constant shear force at 15% and 30% of maximal voluntary contraction (MVC) using one foot. Visual feedback of shear force magnitude was provided for the first 5s, then turned off for 30s. During the 30% MVC task, we observed parallel drops in active shear and vertical force magnitudes leading to consistent drifts in the resultant force magnitude, not in its direction. Force matching by the other foot resulted in significantly lower forces when feedback was available throughout the trial. No feedback was provided for the matching foot. When the matching foot began exerting force, the task foot experienced a notable drop in all force components, with a change in force direction only for the task foot. After this initial drop, the downward drift in the task foot stopped or reversed. Subjects were unaware of these drifts and errors. Our findings suggest that shear force production involves setting a referent coordinate vector, which shows drifts and matching errors, while its direction remains stable. Involvement of the matching foot appears to perturb the neural commands to the task foot, with minor differences observed between feet. The discrepancy between the consistent force drifts and lack of awareness of the drifts indicates a difference between force perception-to-act and perception-to-report.

Recent studies have demonstrated a role for the elastic protein titin in active muscle, but the mechanisms by which titin plays this role remain to be elucidated. In active muscle, Ca2+-binding has been shown to increase titin stiffness, but the observed increase is too small to explain the increased stiffness of parallel elastic elements upon muscle activation. We propose a ‘winding filament’ mechanism for titin's role in active muscle. First, we hypothesize that Ca2+-dependent binding of titin's N2A region to thin filaments increases titin stiffness by preventing low-force straightening of proximal immunoglobulin domains that occurs during passive stretch. This mechanism explains the difference in length dependence of force between skeletal myofibrils and cardiac myocytes. Second, we hypothesize that cross-bridges serve not only as motors that pull thin filaments towards the M-line, but also as rotors that wind titin on the thin filaments, storing elastic potential energy in PEVK during force development and active stretch. Energy stored during force development can be recovered during active shortening. The winding filament hypothesis accounts for force enhancement during stretch and force depression during shortening, and provides testable predictions that will encourage new directions for research on mechanisms of muscle contraction.

Rehabilitation from musculoskeletal injuries focuses on reestablishing and monitoring muscle activation patterns to accurately produce force. The aim of this study is to explore the use of a novel low-powered wearable distributed Simultaneous Musculoskeletal Assessment with Real-Time Ultrasound (SMART-US) device to predict force during an isometric squat task. Participants (N = 5) performed maximum isometric squats under two medical imaging techniques; clinical musculoskeletal motion mode (m-mode) ultrasound on the dominant vastus lateralis and SMART-US sensors placed on the rectus femoris, vastus lateralis, medial hamstring, and vastus medialis. Ultrasound features were extracted, and a linear ridge regression model was used to predict ground reaction force. The performance of ultrasound features to predict measured force was tested using either the Clinical M-mode, SMART-US sensors on the vastus lateralis (SMART-US: VL), rectus femoris (SMART-US: RF), medial hamstring (SMART-US: MH), and vastus medialis (SMART-US: VMO) or utilized all four SMART-US sensors (Distributed SMART-US). Model training showed that the Clinical M-mode and the Distributed SMART-US model were both significantly different from the SMART-US: VL, SMART-US: MH, SMART-US: RF, and SMART-US: VMO models (p < 0.05). Model validation showed that the Distributed SMART-US model had an R2 of 0.80 ± 0.04 and was significantly different from SMART-US: VL but not from the Clinical M-mode model. In conclusion, a novel wearable distributed SMART-US system can predict ground reaction force using machine learning, demonstrating the feasibility of wearable ultrasound imaging for ground reaction force estimation.

Kinesin motors use ATP to produce force in cells, yet the conformational changes that generate force remain uncertain. Here, we report structural and mechanistic insights into a minus-end-directed kinesin-14 that exhibits increased mechanical output – the variant motor binds microtubules more tightly and moves with faster velocity than wild type. High-resolution structures, together with molecular dynamics simulations, reveal previously unobserved transitions in the nucleotide hydrolysis cycle. ADP release, triggered by microtubule binding, is coupled to twisting of the central β-sheet and stabilization of the stalk prior to the power stroke. ATP binding induces stalk fluctuations and a swing of the neck mimic, an element analogous to the kinesin-1 neck linker, resembling neck linker docking in plus-end-directed kinesins. The power stroke, characterized by a large stalk rotation, is followed by motor detachment from microtubules. The subsequent recovery stroke occurs while the motor is bound to ADP and free Pi, accompanied by β-strand-to-loop transitions, or β-sheet melting, implying that β-sheet refolding facilitates Pi release. The observed twisting and melting identify the central β-sheet as the long-sought elastic element or spring required for motor force production. The transitions we observe in kinesin-14 may also apply to other kinesins – this remains to be tested.

Unaccustomed and/or strenuous eccentric contractions are known to cause delayed-onset muscle soreness. In spite of this fact, their exact cause and mechanism have been unknown for more than 120 years. The exploration of the diverse functionality of the Piezo2 ion channel, as the principal proprioceptive component, and its autonomously acquired channelopathy may bring light to this apparently simple but mysterious pain condition. Correspondingly, the neurocentric non-contact acute compression axonopathy theory of delayed-onset muscle soreness suggests two damage phases affecting two muscle compartments, including the intrafusal (within the muscle spindle) and the extrafusal (outside the muscle spindle) ones. The secondary damage phase in the extrafusal muscle space is relatively well explored. However, the suggested primary damage phase within the muscle spindle is far from being entirely known. The current manuscript describes how the proposed autonomously acquired Piezo2 channelopathy-induced primary damage could be the initiating transient neural switch in the unfolding of delayed-onset muscle soreness. This primary damage results in a transient proprioceptive neural switch and in a switch from quantum mechanical free energy-stimulated ultrafast proton-coupled signaling to rapid glutamate-based signaling along the muscle–brain axis. In addition, it induces a transient metabolic switch or, even more importantly, an energy generation switch in Type Ia proprioceptive terminals that eventually leads to a transient glutaminolysis deficit and mitochondrial deficiency, not to mention a force generation switch. In summary, the primary damage or switch is likely an inward unidirectional proton pathway reversal between Piezo2 and its auxiliary ligands, leading to acquired Piezo2 channelopathy.

The concept of synergies has been used to address the grouping of motor elements contributing to a task with the covariation of these elements reflecting task stability. This concept has recently been extended to groups of motor units with parallel scaling of the firing frequencies with possible contributions of intermittent recruitment (MU-modes) in compartmentalized flexor and extensor muscles of the forearm stabilizing force magnitude in finger pressing tasks. Here, we directly test for the presence and behavior of MU-modes in the tibialis anterior, a non-compartmentalized muscle. Ten participants performed an isometric cyclical dorsiflexion force production task at 1 Hz between 20 and 40% of maximal voluntary contraction and electromyographic (EMG) data were collected from two high-density wireless sensors placed on the skin over the right tibialis anterior. EMG data were decomposed into individual motor unit frequencies and resolved into sets of MU-modes. Inter-cycle analysis of MU-mode magnitudes within the framework of the uncontrolled manifold (UCM) hypothesis was used to quantify force-stabilizing synergies. Two or three MU-modes were identified in all participants and trials accounting, on average, for 69% of variance and were robust to cross-validation measurements. Strong dorsiflexion force-stabilizing synergies in the space of MU-modes were present in all participants and for both electrode locations as reflected in variance within the UCM (median 954, IQR 511–1924) exceeding variance orthogonal to the UCM (median 5.82, IQR 2.9–17.4) by two orders of magnitude. In contrast, MU-mode-stabilizing synergies in the space of motor unit frequencies were not present. This study offers strong evidence for the existence of synergic control mechanisms at the level of motor units independent of muscle compartmentalization, likely organized within spinal cord circuitry.