Biology subjects

Herzog, W.

Publications and source records attributed to Herzog, W..

11 recordsLinked to original sources

bioRxiv2026

Sarcomere length, fascicle length, and serial sarcomere number are preserved in paretic hindlimb muscles following chronic stroke in rats despite persistent motor impairment

Stroke causes motor impairments that are commonly attributed to altered neural control, but chronic changes in neural activation and muscle use may also influence skeletal muscle structure. This study examined whether chronic stroke alters sarcomere length and dispersion, fascicle length, or serial sarcomere number in adult skeletal muscle. Twenty-four female Sprague-Dawley rats underwent photothrombotic stroke or sham surgery. Limb-specific motor impairment was assessed longitudinally using a beam traversal task. At 4.5 months post-surgery, the lateral gastrocnemius and extensor digitorum longus muscles were harvested from paretic and non-paretic limbs. We measured fascicle length directly from isolated fascicle bundles and quantified sarcomere length and dispersion using laser diffraction. Stroke animals exhibited persistent impairment of the paretic limb during beam traversal with elevated misstep rates. Despite this persistent motor impairment, sarcomere length and dispersion did not differ between stroke and sham animals or between limbs. Fascicle length and serial sarcomere number were greater in stroke than sham animals, but these differences were not limb-specific and were therefore unlikely to reflect stroke-related changes. Fascicle length, sarcomere length and dispersion, and serial sarcomere number differed between the lateral gastrocnemius and extensor digitorum longus, consistent with differences in architecture or relative length at the selected joint angles. These findings indicate that persistent neural impairment following adult-onset stroke does not necessarily result in substantial changes in sarcomere length or sarcomeres in series. Instead, sarcomere changes may depend on additional factors, including the timing of neural injury relative to growth and the mechanical environment experienced by the muscle.

physiology↗

bioRxiv2026

Force sharing between plantarflexor muscles in sheep during treadmill gait

Muscle force sharing during locomotion is influenced by the mechanical demands of movement and the contractile properties of synergistic muscles. In cats, plantarflexor muscles exhibit distinct functional specialization, with the slow-fibred soleus maintaining relatively constant force across conditions while faster muscles such as the plantaris and gastrocnemius increase force production with increasing locomotor demand. However, it remains unclear whether similar force-sharing patterns occur in larger animals with different musculoskeletal designs. Therefore, the purpose of this study was to examine force sharing between the superficial digital flexor (SDF) and medial gastrocnemius (MG) muscles during treadmill locomotion in sheep. Tendon buckle force transducers were surgically implanted on the SDF and MG tendons of seven sheep, and in vivo muscle forces were recorded during walking and trotting across different speeds and inclines. Both muscles increased force with increasing speed and incline; however, speed had a substantially greater effect than incline. The SDF consistently produced greater absolute force than the MG across all conditions, whereas the MG exhibited slightly larger relative increases in force with increasing speed. Time to peak force decreased with increasing speed in both muscles, although the SDF reached peak force later in stance than the MG across conditions. In contrast to the distinct specialization observed in cats, neither muscle displayed a relatively condition-independent, soleus-like force contribution. These findings suggest that force sharing in sheep is more distributed across synergistic muscles and may reflect the influence of musculoskeletal design, tendon compliance, and mixed fibre-type composition on muscle function in larger species.

bioengineering↗

bioRxiv2025

Pericellular Matrix Proteoglycan Content is Less Affected in The Mid-Zone Cartilage in Early Post-Traumatic Osteoarthritis

Proteoglycan content changes in articular cartilage during post-traumatic osteoarthritis affect both chondrocyte biomechanics and tissue health. Previously, we found that four weeks after anterior cruciate ligament transection (ACLT) in rabbits, proteoglycan loss was less pronounced in the pericellular matrix (PCM) than in the extracellular matrix (ECM), resulting in a greater PCM-to-ECM proteoglycan content ratio compared to controls. Here, we investigate whether this pattern is already present two weeks post-ACLT and whether changes in the proteoglycan ratio relate to cell volumetric strain in the superficial zone during tissue loading. Unilateral ACLT was performed in eight skeletally mature rabbits. Two weeks post-surgery, cartilage from all load-bearing sites of the operated and contralateral knees were collected. Age-matched, non-operated knees from separate animals served as controls. Proteoglycan content in the chondrocyte microenvironment was analyzed in the superficial and middle zones of cartilage via digital densitometry. Volumetric strain of superficial zone cells was measured using two-photon confocal microscopy during indentation. In the superficial zone, the PCM-to-ECM proteoglycan content ratio was greater in the ACLT knees than in controls for the lateral tibial plateau (p = 0.043). However, this was not clearly linked to changes in cell volumetric strain. Interestingly, in the middle zone, the PCM-to-ECM proteoglycan content ratio was greater in the ACLT knees than in controls for the medial femoral condyle, femoral groove, and patella (p < 0.05). These results suggest that, in early post-traumatic osteoarthritis, proteoglycan loss is less severe in the PCM than in the ECM, especially in the middle cartilage zone.

biophysics↗

bioRxiv2024

A Surgical Technique for Individual Control of the Muscles of the Rabbit Lower Hind-limb.

Little is known regarding the precise muscle, bone, and joint actions resulting from individual and simultaneous muscle activation(s) of the lower limb. An in situ experimental approach is described herein to control the muscles of the rabbit lower hind-limb, including the medial and lateral gastrocnemius, soleus, plantaris, and tibialis anterior. The muscles were stimulated using nerve-cuff electrodes placed around the innervating nerves of each muscle. Animals were fixed in a stereotactic frame with the ankle angle free to rotate in the sagittal plane to quantify the behaviour of the lower hind-limb muscles. To demonstrate the efficacy of the experimental technique, isometric plantarflexion torque was measured at a 90 {degrees} ankle joint angle at a stimulation frequency of 100, 60, and 30 Hz. Individual muscle torque and the torque produced during simultaneous activation of all plantarflexor muscles are presented for four animals. These results demonstrate that the experimental approach was reliable, with insignificant variation in torque between repeated contractions. The experimental approach described herein provides the potential for measuring a diverse array of muscle properties which is important to improve our understanding of musculoskeletal biomechanics. HighlightsO_LIA reliable surgical technique was developed for isolated activation of the plantarflexor muscles and the tibialis anterior in the rabbit. Joint torque data are presented for four rabbits at a single joint angle and three stimulation frequencies. C_LI

biophysics↗

bioRxiv2023

Modeling Thick Filament Activation Suggests a Molecular Basis for Force Depression

Multiscale models aiming to connect muscles molecular and cellular function have been difficult to develop, in part, due to a lack of self-consistent multiscale data. To address this gap, we measured the force response from single skinned rabbit psoas muscle fibers to ramp shortenings and step stretches performed on the plateau region of the force-length relationship. We isolated myosin from the same muscles and, under similar conditions, performed single molecule and ensemble measurements of myosins ATP-dependent interaction with actin using laser trapping and in vitro motility assays. We fit the fiber data by developing a partial differential equation model that includes thick filament activation, whereby an increase in force on the thick filament pulls myosin out of an inhibited state. The model also includes a series elastic element and a parallel elastic element. This parallel elastic element models a titin-actin interaction proposed to account for the increase in isometric force following stretch (residual force enhancement). By optimizing the model fit to a subset of our fiber measurements, we specified seven unknown parameters. The model then successfully predicted the remainder of our fiber measurements and also our molecular measurements from the laser trap and in vitro motility. The success of the model suggests that our multiscale data are self-consistent and can serve as a testbed for other multiscale models. Moreover, the model captures the decrease in isometric force observed in our muscle fibers after active shortening (force depression), suggesting a molecular mechanism for force depression, whereby a parallel elastic element combines with thick filament activation to decrease the number of cycling cross-bridges. SIGNIFICANCEConnecting the molecular and cellular scales of muscle contraction would assist in, e.g., the treatment of genetic muscle diseases, the development of heart drugs, and the design of prostheses. The history dependence of muscle contraction, having no clear molecular basis, has remained an obstacle in making this connection for the seventy years since its discovery. We measured the force- and motion-generating capacity of rabbit psoas muscle from the scale of single molecules to single cells. We developed a mathematical model that, when fit to some of the cellular measurements, predicted the remaining cellular measurements and also the molecular measurements. The models ability to capture muscles history dependence suggests a unified description of muscle contraction from the molecular to cellular scale.

biophysics↗

bioRxiv2023

A three filament mechanistic model of musculotendon force and impedance

The force developed by actively lengthened muscle depends on different structures across different scales of lengthening. For small perturbations, the active response of muscle is well captured by a linear-time-invariant (LTI) system: a stiff spring in parallel with a light damper. The force response of muscle to longer stretches is better represented by a compliant spring that can fix its end when activated. Experimental work has shown that the stiffness and damping (impedance) of muscle in response to small perturbations is of fundamental importance to motor learning and mechanical stability, while the huge forces developed during long active stretches are critical for simulating and predicting injury. Outside of motor learning and injury, muscle is actively lengthened as a part of nearly all terrestrial locomotion. Despite the functional importance of impedance and active lengthening, no single muscle model has all of these mechanical properties. In this work, we present the viscoelastic-crossbridge active-titin (VEXAT) model that can replicate the response of muscle to length changes great and small. To evaluate the VEXAT model, we compare its response to biological muscle by simulating experiments that measure the impedance of muscle, and the forces developed during long active stretches. In addition, we have also compared the responses of the VEXAT model to a popular Hill-type muscle model. The VEXAT model more accurately captures the impedance of biological muscle and its responses to long active stretches than a Hill-type model and can still reproduce the force-velocity and force-length relations of muscle. While the comparison between the VEXAT model and biological muscle is favorable, there are some phenomena that can be improved: the low frequency phase response of the model, and a mechanism to support passive force enhancement.

bioengineering↗

bioRxiv2023

Can a Simple Phenomenological Model Explain the Mechanics of Eccentric Contractions?

Notwithstanding decades of research, predictions from the existing muscle models on eccentric contraction remain elusive. This study aimed to test the possibility that a relatively simple phenomenological muscle model, based on an adapted Hill-type muscle model with some novel assumptions, can capture the mechanics of eccentric contractions. The result of the simulations, although preliminary, support the potential of the proposed model in predicting the mechanics of eccentric contraction.

physiology↗

bioRxiv2021

A musculoskeletal finite element model of rat knee joint for evaluating cartilage biomechanics during gait

Abnormal loading of the knee due to injuries or obesity is thought to contribute to the development of osteoarthritis (OA). Small animal models have been used for studying OA progression mechanisms. However, numerical models to study cartilage responses under dynamic loading in preclinical animal models have not been developed. Here we present a musculoskeletal finite element (FE) model of a rat knee joint to evaluate cartilage biomechanical responses during a gait cycle. The rat knee joint geometries were obtained from a 3-D MRI dataset and the boundary conditions regarding loading in the joint were extracted from a musculoskeletal model of the rat hindlimb. The fibril-reinforced poroelastic (FRPE) properties of the rat cartilage were derived from data of mechanical indentation tests. Our numerical results showed the relevance of simulating anatomical and locomotion characteristics in the rat knee joint for estimating tissue responses such as contact pressures, stresses, strains, and fluid pressures. We found that the contact pressure and maximum principal strain were virtually constant in the medial compartment whereas they showed the highest values at the beginning of the gait cycle in the lateral compartment. Furthermore, we found that the maximum principal stress increased during the stance phase of gait, with the greatest values at midstance. We anticipate that our approach serves as a first step towards investigating the effects of gait abnormalities on the adaptation and degeneration of rat knee joint tissues and could be used to evaluate biomechanically-driven mechanisms of the progression of OA as a consequence of joint injury or obesity. Author SummaryOsteoarthritis is a disease of the musculoskeletal system which is characterized by the degradation of articular cartilage. Changes in the knee loading after injuries or obesity contribute to the development of cartilage degeneration. Since injured cartilage cannot be reversed back to intact conditions, small animal models have been widely used for investigating osteoarthritis progression mechanisms. Moreover, experimental studies have been complemented with numerical models to overcome inherent limitations such as cost, difficulties to obtain accurate measures and replicate degenerative situations in the knee joint. However, computational models to study articular cartilage responses under dynamic loading in small animal models have not been developed. Thus, here we present a musculoskeletal finite element model of a rat knee joint to evaluate cartilage biomechanical responses during gait. Our computational model considers both the anatomical and locomotion characteristics of the rat knee joint for estimating mechanical responses in the articular cartilage. We suggest that our approach can be used to investigate tissue adaptations based on the mechanobiological responses of the cartilage to prevent the progression of osteoarthritis.

bioengineering↗

bioRxiv2021

Generation of specialized blood vessels through transdifferentiation of lymphatic endothelial cells

The lineage and developmental trajectory of a cell are key determinants of cellular identity. Yet, the functional relevance of deriving a specific cell type from ontologically distinct progenitors, remains an open question. In the case of the vascular system, blood and lymphatic vessels are composed of endothelial cells (ECs) that differentiate and diversify to cater the different physiological demands of each organ. While lymphatic vessels have been shown to originate from multiple cell sources, lymphatic ECs (LECs) themselves seem to have a unipotent cell fate. In this work we uncover a novel mechanism of blood vessel formation through transdifferentiation of LECs. Using advanced long-term reiterative imaging and lineage-tracing of ECs in zebrafish, from embryonic development through adulthood, we reveal a hitherto unknown process of LEC-to-BEC transdifferentiation, underlying vascularization of the anal fin (AF). Moreover, we demonstrate distinct functional implications for deriving AF vessels from either LECs or BECs, uncovering for the first time a clear link between cell ontogeny and functionality. Molecularly, we identify Sox17 as a negative regulator of lymphatic fate specification, whose specific expression in AF LECs suppresses its lymphatic cell fate. Finally, we show that akin to the developmental process, during adult AF regeneration the vasculature is re-derived from lymphatics, demonstrating that LECs in the mature fish retain both potency and plasticity for generating specialized blood vessels. Overall, our work highlights a novel mechanism of blood vessel formation through LEC trans-differentiation, and provides the first in vivo evidence for a link between cell ontogeny and functionality in ECs.

developmental biology↗

bioRxiv2020

Age-related reductions in the number of serial sarcomeres contribute to shorter fascicle lengths but not elevated passive tension

We investigated age-related changes to fascicle length (FL), sarcomere length (SL), and serial sarcomere number (SSN), and how this affects passive force. Following mechanical testing to determine passive force, the medial gastrocnemius muscle of young (n=9) and old (n=8) Fisher 344BN hybrid rats was chemically fixed at the optimal muscle length for force production; individual fascicles were dissected for length measurement, and laser diffraction was used to assess SL. Old rats had [~]14% shorter FL than young, which was driven by a [~]10% reduction in SSN, with no difference in SL ([~]4%). Passive force was greater in the old compared to young rats at long muscle lengths. Shorter FL and reduced SSN in the old rats could not entirely explain increased passive forces for absolute length changes, owing to a slight reduction in SL in old, resulting in similar SL at long muscle lengths. Summary StatementThis study sought to explain the increased passive tension observed for muscles of older individuals owing to age-related changes to muscle architecture.

physiology↗

bioRxiv2020

Automated analysis of rabbit knee calcified cartilage morphology using micro-computed tomography and deep learning segmentation

PurposeOnly little is known how calcified cartilage (CC) structure changes during exercise, aging and disease. CC thickness (CC.Th) can be analyzed using conventional histological sections. Micro-computed tomography (CT) allows for three-dimensional (3D) imaging of mineralized tissues, however, the segmentation between bone and CC is challenging. Here, we present state-of-the-art deep learning segmentation for CT images to enable assessment of CC morphology. MethodsSixteen knees from twelve New Zealand White rabbits were dissected into osteochondral samples from six anatomical regions: lateral and medial femoral condyles, lateral and medial tibial plateaus, femoral groove and patella (n = 96). Samples were imaged with CT and processed for conventional histology. Manually segmented CC from the histology and reconstructed CT images was used as the gold standard to train segmentation models with different encoder-decoder architectures. The models with the greatest out-of-fold evaluation Dice score were used for automated CC.Th analysis. Subsequently, the automated CC.Th analysis was compared across a total of 24 regions, co-registered between the imaging modalities, using Pearson correlation and Bland-Altman analyses. Finally, the anatomical variation in CC.Th was assessed via a Linear Mixed Model analysis. ResultsThe best segmentation models yielded average Dice scores of 0.891 and 0.807 for histology and CT segmentation, respectively. The correlation between the co-registered regions across the modalities was strong (r = 0.897). The Bland-Altman analysis yielded a bias of 21.9 m and a standard deviation of 21.5 m between the methods. Finally, both methods could separate the CC morphology between the patella, femoral, and tibial regions (p < 0.001). ConclusionThe presented method allows for ex vivo 3D assessment of CC.Th in an automated and non-destructive manner. We demonstrated its utility by quantifying CC.Th in different anatomical regions. CC.Th was the thickest in the patella and the thinnest in the tibial plateau. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/260992v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@19b351aorg.highwire.dtl.DTLVardef@bb6efforg.highwire.dtl.DTLVardef@1744ba0org.highwire.dtl.DTLVardef@1113de_HPS_FORMAT_FIGEXP M_FIG C_FIG We present a CT-based method with deep learning segmentation for analyzing calcified cartilage thickness (CC.Th). The method is compared throughout the study against conventional histology. The comparison against co-registered regions yielded a strong Pearson correlation (r = 0.90). Both methods were able to separate the CC.Th properties between tibia, femur, and patella.

bioinformatics↗