Muscle Model Research Articles

Muscle-like Scaffolds for Biomechanical Stimulation in a Custom-Built Bioreactor.

Tissue engineering aims to develop in-vitro substitutes of native tissues. One approach of tissue engineering relies on using bioreactors combined with biomimetic scaffolds to produce study models or in-vitro substitutes. Bioreactors provide control over environmental parameters, place and hold a scaffold under desired characteristics, and apply mechanical stimulation to scaffolds. Polymers are often used for fabricating tissue-engineering scaffolds. In this study, polycaprolactone (PCL) collagen-coated microfilament scaffolds were cell-seeded with C2C12 myoblasts; then, these were grown inside a custom-built bioreactor. Cell attachment and proliferation on the scaffolds were investigated. A loading pattern was used for mechanical stimulation of the cell-seeded scaffolds. Results showed that the microfilaments provided a suitable scaffold for myoblast anchorage and that the custom-built bioreactor provided a qualified environment for the survival of the myoblasts on the polymeric scaffold. This PCL-based microfilament scaffold located inside the bioreactor proved to be a promising structure for the study of skeletal muscle models and can be used for mechanical stimulation studies in tissue engineering applications.

The effect of the 2-UPS/RR ankle rehabilitation robot with coupling biomechanical model on muscle behaviors.

With the popularization of biomechanical simulation technology, aiming at the rehabilitation of ankle joint injury, we imported simplified model of proposed 2-UPS/RR (two identical unconstraint kinematic branches with a universal-prismatic-spherical (UPS) structure and two rotating pair (R)) ankle rehabilitation robot into AnyBody Modeling System. Therefore, a human-machine model was established using the HILL-type muscle model and muscle recruitment criteria. This paper investigated the effects of rehabilitation trajectories on biomechanical response during rehabilitation. Additionally, three main lower limb muscles (soleus, peroneal brevis, and extensor digitorum longus) were examined under different rehabilitation trajectories (plantar dorsiflexion, varus or valgus, and compound movement) in the present study. Based on the biomechanical response of lower limbs, the results showed that different muscles had different sensitivities to the change of rehabilitation trajectories. The correlation coefficient between joint force and plantar dorsiflexion angle reached 0.99 (P < 0.01), indicating that the change of joint force was mainly dominated by plantar dorsiflexion/plantar flexion, but also affected by varus or valgus. Safe rehabilitation training can be achieved by controlling the designed 2-UPS/RR rehabilitation robot. The behavior of muscle force and joint force under different rehabilitation trajectories can meet the needs of rehabilitation and treatment of joint diseases, and provide more reasonable suggestions for early rehabilitation.

Simulation on control system of the parallel ankle rehabilitation mechanism driven by Pneumatic Artificial Muscles

The ankle is the most weight-bearing joint in the body, which plays a vital role in ensuring people’s walking. Aiming at the problems of complex mechanism, rigid drive and difficult control of the current ankle joint rehabilitation equipment, a 3-SPS/S type ankle parallel rehabilitation mechanism based on pneumatic artificial muscles is developed, and a self-tuning PID controller based on BP neural network is proposed to improve the accuracy of the control system. According to the static characteristics of the pneumatic artificial muscle, the physicians mathematical model of the artificial muscle is optimized, the kinematic position inverse solution of the ankle joint parallel rehabilitation mechanism is analysed and the control system is established. Combined with traditional PID control and BP neural network control algorithm, the BP_PID controller is completed, the control system is simulated and analysed. The simulation results show that BP_PID controller can meet design requirements for the ankle joint parallel rehabilitation mechanism, and is obviously superior to the PID controller in response speed and control accuracy.

Differentiable Simulation of Inertial Musculotendons

We propose a simple and practical approach for incorporating the effects of muscle inertia, which has been ignored by previous musculoskeletal simulators in both graphics and biomechanics. We approximate the inertia of the muscle by assuming that muscle mass is distributed along the centerline of the muscle. We express the motion of the musculotendons in terms of the motion of the skeletal joints using a chain of Jacobians, so that at the top level, only the reduced degrees of freedom of the skeleton are used to completely drive both bones and musculotendons. Our approach can handle all commonly used musculotendon path types, including those with multiple path points and wrapping surfaces. For muscle paths involving wrapping surfaces, we use neural networks to model the Jacobians, trained using existing wrapping surface libraries, which allows us to effectively handle the Jacobian discontinuities that occur when musculotendon paths collide with wrapping surfaces. We demonstrate support for higher-order time integrators, complex joints, inverse dynamics, Hill-type muscle models, and differentiability. In the limit, as the muscle mass is reduced to zero, our approach gracefully degrades to traditional simulators without support for muscle inertia. Finally, it is possible to mix and match inertial and non-inertial musculotendons, depending on the application.

TBBPA induces inflammation, apoptosis, and necrosis of skeletal muscle in mice through the ROS/Nrf2/TNF-α signaling pathway

Tetrabromobisphenol A (TBBPA) is present in large quantities in the environment due to its widespread use. And TBBPA is capable of accumulating in animals, entering the ecological chain and causing widespread damage to organisms. TBBPA is capable of causing the onset of oxidative stress, which induces tissue damage and cell death, which in turn affects the physiological function of tissues. Skeletal muscle is a critical tissue for maintaining growth, movement, and health in the body. However, the mechanism of TBBPA-induced skeletal muscle injury remains unclear. In this study, we constructed mouse skeletal muscle models (10, 20, and 40 mg/kg TBBPA) and mouse myoblasts (C2C12) cell models (2,4, and 8 μg/L TBBPA) at different concentrations. The results of this experiment showed that under TBBPA treatment, the levels of reactive oxygen species (ROS) and Malondialdehyde (MDA) in mouse skeletal and C2C12 cells were increased significantly, but the activities of some antioxidant enzymes decreased. TBBPA can inhibit Nuclear factor E2-related factor 2 (Nrf2) entry into the nucleus, thus affecting the expression of the Nrf2 downstream factors. With the increase of TBBPA concentration, the expression levels of inflammatory factors were significantly increased, while the anti-apoptotic factors were significantly decreased. The expression of pro-apoptotic factors increased in a dose-dependent manner. Programmed necrosis-related factors were also significantly elevated. Our results suggest that TBBPA induces oxidative stress and inflammation, apoptosis, and necrosis in the skeletal muscle of mice by regulating Nrf2/ROS/TNF-α signaling pathway.

Single-nucleus profiling unveils a geroprotective role of the FOXO3 in primate skeletal muscle aging.

Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia, and increases the risk of many aging-related metabolic diseases. Here, we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging. A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types, indicating a higher susceptibility of skeletal muscle fiber to aging. We found a downregulation of FOXO3 in aged primate skeletal muscle, and identified FOXO3 as a hub transcription factor maintaining skeletal muscle homeostasis. Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model, we revealed that silence of FOXO3 accelerates human myotube senescence, whereas genetic activation of endogenous FOXO3 alleviates human myotube aging. Altogether, based on a combination of monkey skeletal muscle and human myotube aging research models, we unraveled the pivotal role of the FOXO3 in safeguarding primate skeletal muscle from aging, providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-related disorders.

Material-based modeling of cavatappi artificial muscles

Soft actuators show much promise for use in bioinspired and biomimetic robotics as they share many similarities with actuation systems found in nature. Twisted and coiled actuators are soft actuators that have been shown to outperform many metrics of biological muscles, leading researchers to derive actuation models for future control and implementation. Although models have been proposed for twisted and coiled carbon nanotubes and polymer fibers, cavatappi artificial muscles—a novel twisted and coiled fluidic soft actuator—have not been modeled yet. This work establishes a framework for modeling cavatappi using the thick-wall pressure vessel stress analysis and the spring theory. The presented model uses the mechanical properties of the precursor drawn material used for fabrication, initial twist (internal fiber angle), muscle geometry, and internal pressure to predict the artificial muscles contraction under different external loads. The model predictions agree with the experimental results for cavatappi of different internal fiber angles and load conditions. Given their potential implementation in bioinspired applications, our model can help better design, optimize, and control the actuation response of cavatappi.

Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology.

McArdle disease is a rare autosomal recessive disorder caused by mutations in the PYGM gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their glycogen stored in skeletal muscle, prompting an exercise intolerance. Currently, there is no treatment for this disease, and the lack of suitable in vitro human models has prevented the search for therapies against it. In this article, we have established the first human iPSC-based model for McArdle disease. For the generation of this model, induced pluripotent stem cells (iPSCs) from a patient with McArdle disease (harbouring the homozygous mutation c.148C&gt;T; p.R50* in the PYGM gene) were differentiated into myogenic cells able to contract spontaneously in the presence of motor neurons and generate calcium transients, a proof of their maturity and functionality. Additionally, an isogenic skeletal muscle model of McArdle disease was created. As a proof-of-concept, we have tested in this model the rescue of PYGM expression by two different read-through compounds (PTC124 and RTC13). The developed model will be very useful as a platform for testing drugs or compounds with potential pharmacological activity.

Understanding altered contractile properties in advanced age: insights from a systematic muscle modelling approach

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.

The necessity of developing a Gait Meridian muscle model

The necessity of developing a Gait Meridian muscle model

Shear wave elastography characterizes passive and active mechanical properties of biceps brachii muscle in vivo

Mechanical characterization of individual muscles in their in vivo environment is not well studied. Shear wave elastography (SWE) as a non-invasive technique was shown to be promising in quantifying the local mechanical properties of skeletal muscles. This study aimed to investigate the mechanics of the biceps brachii muscle (BB) derived from SWE in relation to elbow joint position and contraction intensity during isometric contraction.14 healthy, young subjects participated in the study and five different joint positions (60°–180° elbow angle) were investigated. Shear elastic modulus and surface electromyography (sEMG) of the BB and elbow torque were measured simultaneously, both in passive (i.e., resting) and active states during slow, sub-maximal isometric ramp contractions up to 25%, 50%, and 75% of the maximum voluntary contraction.At passive state, the shear elastic modulus of the BB increased with increasing elbow angle (p < 0.001). Maximum elbow flexion torque was produced at 60° and it decreased with increasing elbow angle (p = 0.001). During sub-maximal contractions, both elbow angle (p < 0.001) and contraction intensity (p < 0.001) had significant effects on the shear elastic modulus but only contraction intensity (p < 0.001) affected sEMG amplitude of the BB. Although torque was decreased at extended elbow positions (150°, 180°), higher active shear elastic modulus of BB muscle was found compared to flexed positions (60°, 90°). Linear regression of the BB sEMG amplitude over elbow torque showed good agreement for all joint positions (R2 between 0.69 and 0.89) while the linear agreement between shear elastic modulus of BB and elbow torque differed between flexed (R2 = 0.70 at 60° and R2 = 0.79 at 90°) and extended positions (with the lowest R2 = 0.57 at 150°).We conclude that using SWE, we can detect length-dependent mechanical changes of BB both in passive and active states. More importantly, SWE can be used to characterize active muscle properties in vivo. The present findings have critical importance for developing muscle stiffness as a measure of individual muscle force to validate muscle models and using SWE in clinical diagnostics.

Design and transmission modeling of a soft elbow exosuit using double artificial tendon system

Daily life would be affected if the upper extremity is injured, especially for people with spinal cord injury, stroke and other neuromuscular disorders. In order to assist in the rehabilitation of these movement disorders, exoskeleton robots are developed. Based on the muscular length relationship and the Hill-type muscle model, a lightweight, soft exosuit is designed for elbow flexion and extension. The exosuit is composed of an actuation box and a wearing sleeve. The power is transmitted from the actuation box to the sleeve utilizing an artificial tendon transmission system. The detailed mechanism design is introduced, and the mathematical double artificial tendon transmission model is developed. Experiments and related simulations are followed to validate the model. The prototype of the soft exosuit is tested on a male subject, and the results indicate that the soft exosuit is capable and effective in helping the elbow joint with flexion and extension.

CRISPR-mediated correction of skeletal muscle Ca2+ handling in a novel DMD patient-derived pluripotent stem cell model

Mutations in the dystrophin gene cause the most common and currently incurable Duchenne muscular dystrophy (DMD) characterized by progressive muscle wasting. Although abnormal Ca2+ handling is a pathological feature of DMD, mechanisms underlying defective Ca2+ homeostasis remain unclear. Here we generate a novel DMD patient-derived pluripotent stem cell (PSC) model of skeletal muscle with an isogenic control using clustered regularly interspaced short palindromic repeat (CRISPR)-mediated precise gene correction. Transcriptome analysis identifies dysregulated gene sets in the absence of dystrophin, including genes involved in Ca2+ handling, excitation-contraction coupling and muscle contraction. Specifically, analysis of intracellular Ca2+ transients and mathematical modeling of Ca2+ dynamics reveal significantly reduced cytosolic Ca2+ clearance rates in DMD-PSC derived myotubes. Pharmacological assays demonstrate Ca2+ flux in myotubes is determined by both intracellular and extracellular sources. DMD-PSC derived myotubes display significantly reduced velocity of contractility. Compared with a non-isogenic wildtype PSC line, these pathophysiological defects could be rescued by CRISPR-mediated precise gene correction. Our study provides new insights into abnormal Ca2+ homeostasis in DMD and suggests that Ca2+ signaling pathways amenable to pharmacological modulation are potential therapeutic targets. Importantly, we have established a human physiology-relevant in vitro model enabling rapid pre-clinical testing of potential therapies for DMD.

Hill-type, bioinspired actuation delivers energy economy in DC motors

Electromagnetic motors convert stored energy to mechanical work through a linear force–velocity (FV) relationship. In biological systems, however, muscle actuation is characterized by the hyperbolic FV mechanisms of the Hill muscle—in which a parameter α characterizes the degree of nonlinearity. Previous work has shown that bioinspiration in human-engineered systems can contribute favorable mechanical attributes—such as energy efficiency, self-stability, and flexibility, among others. In this study, we first construct an easily amendable, bioinspired electromagnetic motor which produces FV curves that mimic the Hill model of muscle with a high degree of accuracy. A proportional-integral-differential (PID) controller converges the characteristically linear FV relationship of a DC motor to nonlinear Hill-type force outputs. The bioinspired electric motor does a fixed amount of work by lifting a 147.5 g mass, and we record the translational velocity of the mass and the nonlinear applied force of the motor. Under optimized gain coefficients in the PID, the bioinspired motor achieves agreement of with the Hill muscle model. Studies have shown that designing biologically inspired actuators produce comparatively energy efficient systems. We investigate the energy economy of actuating our motor with nonlinear, Hill-type forces in direct comparison with conventional linear FV actuation techniques. We find that the bioinspired motor delivers energy economy with respect to energy consumption and conversion: the nonlinear, Hill-type DC motor reduces the energetic cost of actuation when delivering a fixed amount of mechanical work.

Hierarchical Motion Learning for Goal-Oriented Movements With Speed-Accuracy Tradeoff of a Musculoskeletal System.

Generating various goal-oriented movements via the flexible muscle model of the musculoskeletal system as fast and accurately as possible is a pressing problem, which is also the basis of most human adaptive behaviors, such as reaching, catching, interception, and pointing. This article focuses on the adaptive motion generation of fast goal-oriented motion on the musculoskeletal system by implementing the speed-accuracy tradeoff (SAT) in a hierarchical motion learning framework. First, we introduce Fitts' Law into the modified basal ganglia circuit-inspired iterative decision-making model for achieving dynamic and adaptive decision making. Then, as a time constraint, the decision is decomposed into a series of supervised terms by the proposed striatal FSI-SPN interneuron circuit-inspired velocity modulator to implement the tradeoff smoothly on the musculoskeletal system. Finally, an improved policy gradient algorithm is suggested to generate the muscle excitations of the modulated motion via the proposed muscle co-contraction policy, which promotes general cooperation between flexor and extensor muscles. In experiments, a redundant musculoskeletal arm model is trained to perform the adaptive quick pointing movements. By combining the muscle co-contraction policy with SAT, our algorithm shows the most efficient training and the best performance in the adaptive motion generation among the other three popular reinforcement learning algorithms on the musculoskeletal model.

Design and Control of a Pneumatic Muscle Servo Drive Containing Its Own Pneumatic Muscles

This article presents static and dynamic characteristics of artificial pneumatic muscles. The research stance and the methodology for their determination are described. A mathematical model of a pneumatic muscle has been proposed, having two inputs—the force generated by the muscle and the displacement of the muscle tip, and one output—the valve control voltage. The quality of object mapping was verified by a mathematical model for various trajectories. Then, the control system for the moment servo drive force was composed of two pneumatic muscles working in opposite directions connected by a toothed belt gear. The servo drive was verified and evaluated.

Engineered skeletal muscle recapitulates human muscle development, regeneration and dystrophy.

Human pluripotent stem cell-derived muscle models show great potential for translational research. Here, we describe developmentally inspired methods for the derivation of skeletal muscle cells and their utility in skeletal muscle tissue engineering with the aim to model skeletal muscle regeneration and dystrophy in vitro. Key steps include the directed differentiation of human pluripotent stem cells to embryonic muscle progenitors followed by primary and secondary foetal myogenesis into three-dimensional muscle. To simulate Duchenne muscular dystrophy (DMD), a patient-specific induced pluripotent stem cell line was compared to a CRISPR/Cas9-edited isogenic control line. The established skeletal muscle differentiation protocol robustly and faithfully recapitulates critical steps of embryonic myogenesis in two-dimensional and three-dimensional cultures, resulting in functional human skeletal muscle organoids (SMOs) and engineered skeletal muscles (ESMs) with a regeneration-competent satellite-like cell pool. Tissue-engineered muscle exhibits organotypic maturation and function (up to 5.7±0.5mN tetanic twitch tension at 100Hz in ESM). Contractile performance could be further enhanced by timed thyroid hormone treatment, increasing the speed of contraction (time to peak contraction) as well as relaxation (time to 50% relaxation) of single twitches from 107±2 to 75±4ms (P<0.05) and from 146±6 to 100±6ms (P<0.05), respectively. Satellite-like cells could be documented as largely quiescent PAX7+ cells (75±6% Ki67- ) located adjacent to muscle fibres confined under a laminin-containing basal membrane. Activation of the engineered satellite-like cell niche was documented in a cardiotoxin injury model with marked recovery of contractility to 57±8% of the pre-injury force 21days post-injury (P<0.05 compared to Day 2 post-injury), which was completely blocked by preceding irradiation. Absence of dystrophin in DMD ESM caused a marked reduction of contractile force (-35±7%, P<0.05) and impaired expression of fast myosin isoforms resulting in prolonged contraction (175±14ms, P<0.05 vs. gene-edited control) and relaxation (238±22ms, P<0.05 vs. gene-edited control) times. Restoration of dystrophin levels by gene editing rescued the DMD phenotype in ESM. We introduce human muscle models with canonical properties of bona fide skeletal muscle in vivo to study muscle development, maturation, disease and repair.

Insulin resistance promotes extracellular BCAA accumulation without altering LAT1 content, independent of prior BCAA treatment in a myotube model of skeletal muscle

PurposeType 2 diabetes is characterized by reduced insulin sensitivity which correlates with increased circulating BCAA. These experiments investigated the effects of insulin resistance with and without excess BCAA on myotube insulin sensitivity and L-type amino acid transporter-1 (LAT1). MethodsC2C12 myotubes were treated with or without excess BCAA for 1 or 6 days, both with and without insulin resistance. Western blot was used to assess insulin sensitivity and LAT1 content. Liquid chromatography-mass spectrometry was used to evaluate BCAA media content. ResultsInsulin resistance was associated with significantly increased extracellular BCAA accumulation independent of LAT1 content. Conversely, prior BCAA treatment was not associated with extracellular BCAA accumulation regardless of level of insulin sensitivity. ConclusionThese data suggest insulin resistance, but not BCAA treatment, promotes extracellular BCAA accumulation independent of changes in LAT1 content, implicating insulin resistance as a causal agent of extracellular BCAA accumulation.

Validate the force-velocity relation of the Hill's muscle model from a molecular perspective.

Validate the force-velocity relation of the Hill's muscle model from a molecular perspective.

Effects of sodium chloride and sodium tripolyphosphate on the prooxidant properties of hemoglobin in washed turkey muscle system.

This study examined the effects of sodium chloride (NaCl) and sodium tripolyphosphate (STPP) on lipid oxidation induced by oxyhemoglobin (oxyHb) in washed turkey muscle (WTM) model. To explore the reasons for observed effects, the pro-oxidant abilities of Hb derivatives (e.g., metHb, oxyHb, hemin, Fe2+, and Fe3+), pH change, and antioxidation of Hb in the presence of NaCl or STPP were also analyzed. The observed lipid oxidation capacity in WTM followed the order metHb>hemin>oxyHb>Fe2+ > Fe3+. Added Fe2+ accelerated auto-oxidation of oxyHb and oxyHb-mediated lipid oxidation. Hb auto-oxidation to metHb increased as the pH decreased from 6.6 to 5.0. NaCl promoted oxyHb-mediated lipid oxidation due to NaCl causing decreased pH value and increased formation of metHb. STPP inhibited oxyHb-mediated lipid oxidation and weakened the pro-oxidative effect of NaCl. This could be attributed to STPP increasing the pH, inactivating free iron, and inhibiting formation of metHb.