Network model of skeletal muscle cell signalling predicts differential responses to endurance and resistance exercise training.

Exercise-induced muscle adaptations vary based on exercise modality and intensity. We constructed a signalling network model from 87 published studies of human or rodent skeletal muscle cell responses to endurance or resistance exercise in vivo or simulated exercise in vitro. The network comprises 259 signalling interactions between 120 nodes, representing eight membrane receptors and eight canonical signalling pathways regulating 14 transcriptional regulators, 28 target genes and 12 exercise-induced phenotypes. Using this network, we formulated a logic-based ordinary differential equation model predicting time-dependent molecular and phenotypic alterations following acute endurance and resistance exercises. Compared with nine independent studies, the model accurately predicted 18/21 (85%) acute responses to resistance exercise and 12/16 (75%) acute responses to endurance exercise. Detailed sensitivity analysis of differential phenotypic responses to resistance and endurance training showed that, in the model, exercise regulates cell growth and protein synthesis primarily by signalling via mechanistic target of rapamycin, which is activated by Akt and inhibited in endurance exercise by AMP-activated protein kinase. Endurance exercise preferentially activates inflammation via reactive oxygen species and nuclear factor κB signalling. Furthermore, the expected preferential activation of mitochondrial biogenesis by endurance exercise was counterbalanced in the model by protein kinase C in response to resistance training. This model provides a new tool for investigating cross-talk between skeletal muscle signalling pathways activated by endurance and resistance exercise, and the mechanisms of interactions such as the interference effects of endurance training on resistance exercise outcomes.

Differential sensitivity to longitudinal and transverse stretch mediates transcriptional responses in mouse neonatal ventricular myocytes.

To identify how cardiomyocyte mechanosensitive signaling pathways are regulated by anisotropic stretch, micropatterned mouse neonatal cardiomyocytes were stretched primarily longitudinally or transversely to the myofiber axis. Four hours of static, longitudinal stretch induced differential expression of 557 genes, compared with 30 induced by transverse stretch, measured using RNA-seq. A logic-based ordinary differential equation model of the cardiac myocyte mechanosignaling network, extended to include the transcriptional regulation and expression of 784 genes, correctly predicted measured expression changes due to anisotropic stretch with 69% accuracy. The model also predicted published transcriptional responses to mechanical load in vitro or in vivo with 63-91% accuracy. The observed differences between transverse and longitudinal stretch responses were not explained by differential activation of specific pathways but rather by an approximately twofold greater sensitivity to longitudinal stretch than transverse stretch. In vitro experiments confirmed model predictions that stretch-induced gene expression is more sensitive to angiotensin II and endothelin-1, via RhoA and MAP kinases, than to the three membrane ion channels upstream of calcium signaling in the network. Quantitative cardiomyocyte gene expression differs substantially with the axis of maximum principal stretch relative to the myofilament axis, but this difference is due primarily to differences in stretch sensitivity rather than to selective activation of mechanosignaling pathways.NEW & NOTEWORTHY Anisotropic stretch applied to micropatterned neonatal mouse ventricular myocytes induced markedly greater acute transcriptional responses when the major axis of stretch was parallel to the myofilament axis than when it was transverse. Analysis with a novel quantitative network model of mechanoregulated cardiomyocyte gene expression suggests that this difference is explained by higher cell sensitivity to longitudinal loading than transverse loading than by the activation of differential signaling pathways.

A new look at an old problem: 3D modeling of accommodation reveals how age-related biomechanical changes contribute to dysfunction in presbyopia.

Presbyopia is an age-related ocular disorder where accommodative ability declines so that an individual's focusing range is insufficient to provide visual clarity for near and distance vision tasks without corrective measures. With age, the eye exhibits changes in biomechanical properties of many components involved in accommodation, including the lens, sclera, and ciliary muscle. Changes occur at different rates, affecting accommodative biomechanics differently, but individual contributions to presbyopia are unknown. We used a finite element model (FEM) of the accommodative mechanism to simulate age-related changes in lens stiffness, scleral stiffness, and ciliary contraction to predict differences in accommodative function. The FEM predicts how ciliary muscle action leads to lens displacement by initializing a tensioned unaccommodated lens (Phase 0) then simulating ciliary muscle contraction in accommodation (Phase 1). Model inputs were calibrated to replicate experimentally measured lens and ciliary muscle in 30-year-old eyes. Predictions of accommodative lens deformation were verified with additional imaging studies. Model variations were created with altered lens component stiffnesses, scleral stiffness, or ciliary muscle section activations, representing fifteen-year incremental age-related changes. Model variations predict significant changes in accommodative function with age-related biomechanical property changes. Lens changes only significantly altered lens thickening with advanced age (46% decrease at 75 years old) while sclera changes produced progressive dysfunction with increasing age (23%, 36%, 49% decrease at 45, 60, and 75 years old). Ciliary muscle changes effected lens position modulation. Model predictions identified potential mechanisms of presbyopia that likely work in combination to reduce accommodative function and could indicate effectiveness of treatment strategies and their dependency on patient age or relative ocular mechanical properties.

Athlete Muscular Phenotypes Identified and Compared with High-Dimensional Clustering of Lower Limb Muscle Volume Measurements.

INTRODUCTION: Athletes use their skeletal muscles to demonstrate performance. Muscle force generating capacity is correlated with volume, meaning that variations in sizes of different muscles may be indicative of how athletes meet different demands in their sports. Medical imaging enables in vivo quantification of muscle volumes; however, muscle volume distribution has not been compared across athletes of different sports. PURPOSE: The goal of this work was to define "muscular phenotypes" in athletes of different sports and compare these using hierarchical clustering. METHODS: Muscle volumes normalized by body mass of athletes (football, baseball, basketball, or track) were compared with control participants to quantify size differences using z -scores. z -Scores of 35 muscles described the pattern of volume deviation within each athlete's lower limb, characterizing their muscular phenotype. Data-driven high-dimensional clustering analysis was used to group athletes presenting similar phenotypes. Efficacy of clustering to identify similar phenotypes was demonstrated by grouping athletes' contralateral limbs before other athletes' limbs. RESULTS: Analyses revealed that athletes did not tend to cluster with others competing in the same sport. Basketball players with similar phenotypes grouped by clustering also demonstrated similarities in performance. Clustering also identified muscles with similar volume variation patterns across athletes, and principal component analysis revealed specific muscles that accounted for most of the variance (gluteus maximus, sartorius, semitendinosus, vastus medialis, vastus lateralis, and rectus femoris). CONCLUSIONS: Athletes exhibit heterogeneous lower limb muscle volumes that can be characterized and compared as individual muscular phenotypes. Clustering revealed that athletes with the most similar phenotypes do not always play the same sport such that patterns of muscular heterogeneity across a group of athletes reflect factors beyond their specific sports.

Personalized volumetric assessment of lower body muscles in patients with knee injuries: A descriptive case series.

BACKGROUND: Patients with knee joint pathology present with variable muscular responses across the muscles of the lower limb and pelvis. Conventional approaches to characterizing muscle function are limited to gross strength assessments that may overlook subtle changes both in the thigh, hip and shank musculature. PURPOSE: To describe individualized patterns of lower extremity muscle volumes in patients with knee pathologies. METHODS: This was a retrospective case series performed in a University medical center. Nine patients diagnosed with meniscus tear recommended to undergo meniscectomy volunteered. Participants underwent 3.0 Tesla magnetic resonance imaging (MRI) of the lower extremities. Thirty-five MRI-derived muscle volumes were compared between limbs and expressed as percentage asymmetry. For additional context, z-scores were also calculated for mass- and height-normalized muscles and pre-determined muscle groupings relative to a normative database. RESULTS: There were no consistent patterns observed when considering between-limb asymmetries among all patients. The ankle musculature (dorsiflexors, plantar flexors, and invertors) was the only muscle group to be consistently smaller than normal for all patients, with the psoas major and flexor hallucis longus being the only individual muscles. The severity or chronicity of injury and presence of surgical intervention did not appear to have a clear effect on muscle volumes. CONCLUSION: Patients with a history of meniscal pathology demonstrate inconsistent patterns of lower extremity muscle volumes about the hip, knee, and ankle between limbs and in comparison to uninjured individuals. These data support the need for individualized assessment and intervention in this population.

A 3D model of the soleus reveals effects of aponeuroses morphology and material properties on complex muscle fascicle behavior.

The soleus is an important plantarflexor muscle with complex fascicle and connective tissue arrangement. In this study we created an image-based finite element model representing the 3D structure of the soleus muscle and its aponeurosis connective tissue, including distinct fascicle architecture of the posterior and anterior compartments. The model was used to simulate passive and active soleus lengthening during ankle motion to predict tissue displacements and fascicle architecture changes. Both the model's initial architecture and changes incurred during passive lengthening were consistent with prior in vivo data from diffusion tensor imaging. Model predictions of active lengthening were consistent with axial plane muscle displacements that we measured in eight subjects' lower legs using cine DENSE (Displacement Encoding with Stimulated Echoes) MRI during eccentric dorsiflexion. Regional strains were variable and nonuniform in the model, but average fascicle strains were similar between the compartments for both passive (anterior: 0.18 ± 0.06, posterior: 0.19 ± 0.05) and active (anterior: 0.12 ± 0.05, posterior: 0.13 ± 0.06) lengthening and were two- to three-times greater than muscle belly strain (0.06). We used additional model simulations to investigate the effects of aponeurosis material properties on muscle deformation, by independently varying the longitudinal or transverse stiffness of the posterior or anterior aponeurosis. Results of model variations elucidate how properties of soleus aponeuroses contribute to fascicle architecture changes. Greater longitudinal stiffness of posterior compared to anterior aponeurosis promoted more uniform spatial distribution of muscle tissue deformation. Reduced transverse stiffness in both aponeuroses resulted in larger differences between passive and active soleus lengthening.

3D Models Reveal the Influence of Achilles Subtendon Twist on Strain and Energy Storage.

The Achilles tendon (AT) has complex function in walking, exchanging energy due to loading by the triceps surae muscles. AT structure comprises three subtendons which exhibit variable twist among themselves and between individuals. Our goal was to create 3D finite element (FE) models to explore AT structure-function relationships. By simulating subtendon loading in FE models with different twisted geometries, we investigated how anatomical variation in twisted tendon geometry impacts fascicle lengths, strains, and energy storage. Three tendon FE models, built with elliptical cross sections based on average cadaver measurements, were divided into subtendons with varied geometric twist (low, medium, and high) and equal proportions. Tendon was modeled as transversely isotropic with fascicle directions defined using Laplacian flow simulations, producing fascicle twist. Prescribed forces, representing AT loading during walking, were applied to proximal subtendon ends, with distal ends fixed, and tuned to produce equal tendon elongation in each case, consistent with ultrasound measurements. Subtendon fascicle lengths were greater than free tendon lengths in all models by 1-3.2 mm, and were longer with greater subtendon twist with differences of 1.2-1.9 mm from low to high twist. Subtendon along-fiber strains were lower with greater twist with differences of 1.4-2.6%, and all were less than free tendon longitudinal strain by 2-5.5%. Energy stored in the AT was also lower with greater twist with differences of 1.8-2.4 J. With greater subtendon twist, similar elongation of the AT results in lower tissue strains and forces, so that longitudinal stiffness of the AT is effectively decreased, demonstrating how tendon structure influences mechanical behavior.

The action of ciliary muscle contraction on accommodation of the lens explored with a 3D model.

The eye's accommodative mechanism changes optical power for near vision. In accommodation, ciliary muscle excursion relieves lens tension, allowing it to return to its more convex shape. Lens deformation alters its refractive properties, but the mechanics of ciliary muscle actions are difficult to intuit due to the complex architecture of the tissues involved. The muscle itself comprises three sections of dissimilarly oriented cells. These cells contract, transmitting forces through the zonule fibers and extralenticular structures. This study aims to create a finite element model (FEM) to predict how the action of the ciliary muscle sections leads to lens displacement. The FEM incorporates initialization of the disaccommodated lens state and ciliary muscle contraction, with three muscle sections capable of independent activation, to drive accommodative movement. Model inputs were calibrated to replicate experimentally measured disaccommodated lens and accommodated ciliary muscle shape changes. Additional imaging studies were used to validate model predictions of accommodative lens deformation. Models were analyzed to quantify mechanical actions of ciliary muscle sections in lens deformation and position modulation. Analyses revealed that ciliary muscle sections act synergistically: the circular section contributes most to increasing lens thickness, while longitudinal and radial sections can oppose this action. Conversely, longitudinal and radial sections act to translate the lens anteriorly with opposition from the circular section. This FEM demonstrates the complex interplay of the three sections of ciliary muscle in deforming and translating the lens during accommodation, providing a useful framework for future investigations of accommodative dysfunction that occurs with age in presbyopia.

Achilles Tendon Morphology Is Related to Triceps Surae Muscle Size and Peak Plantarflexion Torques During Walking in Young but Not Older Adults.

The interaction of the triceps surae muscles and the Achilles tendon is critical in producing the ankle plantarflexion torque required for human walking. Deficits in plantarflexor output are a hallmark of reduced mobility in older adults and are likely associated with changes in the triceps surae muscles that occur with age. Structural differences between young and older adults have been observed in the Achilles tendon and in the triceps surae muscles. However, less is known about how age-related differences in muscle and tendon morphology correspond with each other and, furthermore, how those morphology differences correlate with age-related deficits in function. The goal of this work was to investigate whether there is a correlation between age-related differences in triceps surae muscle size and Achilles tendon cross-sectional area (CSA) and whether either is predictive of ankle plantarflexion torque during walking. We used magnetic resonance imaging (MRI) to measure triceps surae muscle volumes and tendon CSAs in young (n = 14, age: 26 ± 4 years) and older (n = 7, age: 66 ± 5 years) adults, and we determined peak plantarflexion torques during treadmill walking. We found that individual muscle volumes as a percentage of the total triceps surae volume did not differ between young and older adults, though muscle volumes per body size (normalized by the product of height and mass) were smaller in older adults. Achilles tendon CSA was correlated with body size and muscle volumes in young adults but not in older adults. The ratio of tendon CSA to total triceps surae muscle volume was significantly greater in older adults. Peak ankle plantarflexion torque during walking correlated with body size and triceps surae volume in young and older adults but was correlated with tendon CSA only in the young adults. Structure-function relationships that seem to exist between the Achilles tendon and the triceps surae muscles in young adults are no longer evident in all older adults. Understanding mechanisms that determine altered Achilles tendon CSA in older adults may provide insight into age-related changes in function.

MRI-Based Assessment of Lower-Extremity Muscle Volumes in Patients Before and After ACL Reconstruction.

CONTEXT: Study of muscle volumes in patients after anterior cruciate ligament (ACL) injury and reconstruction (ACL-R) is largely limited to cross-sectional assessment of the thigh musculature, which may inadequately describe posttraumatic and postsurgical muscle function. No studies have prospectively examined the influence of ACL injury and reconstruction on lower-extremity muscle volumes. OBJECTIVE: Assess magnetic resonance imaging-derived lower-extremity muscle volumes, and quantify quadriceps strength and activation in patients following ACL injury and reconstruction. DESIGN: Prospective case series. SETTING: Research laboratory and magnetic resonance imaging facility. Patients (or Other Participants): Four patients (2 men and 2 women; age = 27.4 (7.4) y, height = 169.2 (8.1) cm, and mass = 74.3 (18.5) kg) scheduled for ACL-R. INTERVENTION(S): Thirty-five muscle volumes were obtained from a bilateral lower-extremity magnetic resonance imaging before and after ACL-R. MAIN OUTCOME MEASURES: Muscle volumes expressed relative to (1) a normative database presurgery and postsurgery, (2) limb symmetry presurgery and postsurgery, and (3) percentage change presurgery to postsurgery. Quadriceps function was quantified by normalized knee extension maximal voluntary isometric contraction torque and central activation ratio. RESULTS: Involved vastus lateralis and tibialis anterior were consistently smaller than healthy individuals (z < -1 SD) presurgery and postsurgery in all patients. Involved rectus femoris and vastus lateralis were more than 15% smaller than the contralateral limb presurgery, whereas the involved rectus femoris, gracilis, vastus medialis, vastus intermedius, and vastus lateralis muscle volumes exceeded 20% asymmetry postoperatively. Involved gracilis and semitendinosus atrophied more than 30% from presurgery to postsurgery. Involved maximal voluntary isometric contraction torque and central activation ratio increased by 12.7% and 12.5%, respectively, yet strength remained 33.2% asymmetric postsurgery. CONCLUSIONS: Adaptations in lower-extremity muscle volumes are present following ACL injury and reconstruction. Anterior thigh and shank muscles were smaller than healthy individuals, and large asymmetries in quadriceps volumes were observed presurgery and postsurgery. Selective atrophy of the semitendinosus and gracilis occurred following surgery. Volumetric deficits of the quadriceps musculature may exist despite improvements in muscle strength and activation.