Analysis of a muscular control system in human movements

In this work, we have studied a muscular control system under experimental conditions for analyzing the dynamic behavior of individual muscles and theoretical considerations for elucidating its control strategy. Movement of human limbs is achieved by joint torques and each torque is specified as the sum of torques generated by muscle forces. The behavior of individual muscles is controlled by the neural input which is estimated by means of an electromyogram (EMG). In this study, the EMGs for a flexor and an extensor are measured in elbow joint movements and the dynamic behavior of individual muscles is analyzed. As a result, it is verified that both a flexor and an extensor are activated throughout the entire movement and that the activation of muscles is controlled above a specific limit independent of the hand-held load. Subsequently, a system model for simulating elbow joint movements is developed which includes the muscle dynamic relationship between the neural input and the isometric force. The minimum limit of muscle activation that has been confirmed in experiments is provided as a constraint of the neural input and the criterion is defined by a derivative of the isometric force of individual muscles. The optimal trajectories formulated under these conditions are quantitatively compared with the experimentally observed trajectories, and the control strategy of a muscular control system is studied. Finally, a muscular control system in multi-joint arm movements is discussed with regard to the comparative analysis between observed and optimal trajectories. Received: 7 April 1999 / Accepted in revised form: 27 July 1999     

Optimal systems: III. Muscle

The optimal systems approach to the muscular system leads to difficulties since the properties of the muscular system are determined to a great extent by the nature of the contractile unit or molecule. This unit has determined the morphology and dynamic characteristics of muscle, and only smaller order alterations are then possible to adapt muscle to its several functions. A model of the contractile unit is developed that shows agreement with experimental findings with respect to the velocity-load relation, heat effects, and several aspects of knowledge of the structure of the contractile proteins.     

Functional characteristics of dystrophic skeletal muscle: insights from animal models.

Muscular dystrophies are a clinically and genetically heterogeneous group of disorders that show myofiber degeneration and regeneration. Identification of animal models of muscular dystrophy has been instrumental in research on the pathogenesis, pathophysiology, and treatment of these disorders. We review our understanding of the functional status of dystrophic skeletal muscle from selected animal models with a focus on 1) the mdx mouse model of Duchenne muscular dystrophy, 2) the Bio 14.6 delta-sarcoglycan-deficient hamster model of limb-girdle muscular dystrophy, and 3) transgenic null mutant murine lines of sarcoglycan (alpha, beta, delta, and gamma) deficiencies. Although biochemical data from these models suggest that the dystrophin-sarcoglycan-dystroglycan-laminin network is critical for structural integrity of the myofiber plasma membrane, emerging studies of muscle physiology suggest a more complex picture, with specific functional deficits varying considerably from muscle to muscle and model to model. It is likely that changes in muscle structure and function, downstream of the specific, primary biochemical deficiency, may alter muscle contractile properties.     

Modelling concentric contraction of muscle using an improved cross-bridge model.

Despite its overwhelming acceptance in muscle research, the cross-bridge theory does not account for all phenomena observed during muscular contractions. A phenomenon which has received much attention in the biomechanics literature, but has evaded convincing explanation and is not accounted for in the formulation of the classic cross-bridge theory, is the persistent aftereffects of muscular length changes on force production. For example, following muscle shortening, the isometric force of a muscle is depressed for a long time period ( > 5 s) compared to the corresponding isometric force following no length change. In the present study, the classic cross-bridge model was modified in two ways in an attempt to account for the force depressions following muscle shortening. First, the steady-state force depressions following shortening were described by a single scalar variable: the work performed by the muscle during shortening; and second, the dynamic, history-dependent cross-bridge properties were described using a fading memory function. The proposed model was developed and tested for shortening of the cat soleus at constant speeds ranging from 4 to 32 mm/s, for shortening at changing speeds, and for shortening of different magnitudes ranging from 2 to 10 mm. The history-dependent forces during shortening and the steady-state force depressions following shortening were well captured with the modified cross-bridge model. The present model contains two mathematically simple adaptations to the classic cross-bridge model, and is the first such model to account for the long-lasting force depressions following muscle shortening using a single scalar variable.     

Duchenne muscular dystrophy: focus on pharmaceutical and nutritional interventions

Duchenne muscular dystrophy is a lethal X-linked muscle disease resulting from a defect in the muscle membrane protein dystrophin. The absence of dystrophin leads to muscle membrane fragility, muscle death (necrosis) and eventual replacement of skeletal muscle by fat and fibrous connective tissue. Extensive muscle wasting and respiratory failure results in premature death often by the early 20s. This short review evaluates drug and nutritional interventions designed to reduce the severity of muscular dystrophy, while awaiting the outcome of research into therapies to correct the fundamental gene defect. Combinations of dietary supplementation with amino-acids such as creatine, specific anti-inflammatory drugs and perhaps drugs that target ion channels might have immediate realistic clinical benefits although rigorous research is required to determine optimal combinations of such interventions.     

Energy-optimal controls in the mammalian neuromuscular system

The hypothesis is advanced that the specific patterns of motor unit recruitment and stimulation frequencies observed in mammalian skeletal muscle under static isometric contractions are determined by a minimum-energy principle. By performing a constrained energy optimization based on a control model of skeletal muscle comprising three different fibre types, and appropriate expressions for the energy rates, it is indeed possible to obtain detailed predictions of recruitment and stimulation frequency patterns which agree well with the experimentally observed functions, thereby providing strong support for the minimum-energy hypothesis. Since the orderly recruitment sequence determined by the size principle is also, independently, predicted by the minimum-energy principle, it is concluded that there exists a relationship between motor unit size and the myoenergetic properties of the recruited unit. It is suggested that this relationship, together with the possibility of adjusting the relative proportions of the fibre types present in a muscle, constitutes an optimal adaptation of the neuromuscular system for practically all types of muscular performances normally encountered. For various types of muscles, the energy rates as functions of the force output are also discussed.     

Evaluation of the minimum energy hypothesis and other potential optimality criteria for human running

A popular hypothesis for human running is that gait mechanics and muscular activity are optimized in order to minimize the cost of transport (CoT). Humans running at any particular speed appear to naturally select a stride length that maintains a low CoT when compared with other possible stride lengths. However, it is unknown if the nervous system prioritizes the CoT itself for minimization, or if some other quantity is minimized and a low CoT is a consequential effect. To address this question, we generated predictive computer simulations of running using an anatomically inspired musculoskeletal model and compared the results with data collected from human runners. Three simulations were generated by minimizing the CoT, the total muscle activation or the total muscle stress, respectively. While all the simulations qualitatively resembled real human running, minimizing activation predicted the most realistic joint angles and timing of muscular activity. While minimizing the CoT naturally predicted the lowest CoT, minimizing activation predicted a more realistic CoT in comparison with the experimental mean. The results suggest a potential control strategy centred on muscle activation for economical running.     

The association between negative muscle work and pedaling rate.

The objective of this research was to use a pedal force decomposition approach to quantify the amount of negative muscular crank torque generated by a group of competitive cyclists across a range of pedaling rates. We hypothesized that negative muscular crank torque increases at high pedaling rates as a result of the activation dynamics associated with muscle force development and the need for movement control, and that there is a correlation between negative muscular crank torque and pedaling rate. To test this hypothesis, data were collected during 60, 75, 90, 105 and 120 revolutions per minute (rpm) pedaling at a power output of 260 W. The statistical analysis supported our hypothesis. A significant pedaling rate effect was detected in the average negative muscular crank torque with all pedaling rates significantly different from each other (p < 0.05). There was no negative muscular crank torque generated at 60 rpm and negligible amounts at 75 and 90 rpm. But substantial negative muscular crank torque was generated at the two highest pedaling rates (105 and 120 rpm) that increased with increasing pedaling rates. This result suggested that there is a correlation between negative muscle work and the pedaling rates preferred by cyclists (near 90 rpm), and that the cyclists' ability to effectively accelerate the crank with the working muscles diminishes at high pedaling rates.     

Muscular dystrophy of mink: a new animal model.

Muscular dystrophies comprise an important group of inherited disorders of man. Although the disease has been studied extensively, little is known about the underlying primary pathomechanisms. Consequently, treatment of patients is difficult and prognosis is poor. An animal model of muscular dystrophy is a useful research tool for approaching the basic problems of pathogenesis in muscle diseases. An inherited progressive muscular dystrophy of mink which resembles the amyotonic forms of human muscular dystrophy is currently under study. Clinically, the earliest sign is progressive muscular weakness and atrophy. Muscle enzyme activities in serum are usually elevated to pathologic levels. Urinary creatine/creatinine ratio is elevated. Pathologic changes are limited to skeletal muscle and are typical of those seen in amyotonic forms of human muscular dystrophy. These changes include variation in diameter size of muscle fibers, centralized nuclei, floccular and hyaline degeneration of scattered muscle fibers, increase in connective tissue in endomysial and perimysial areas, and regenerative attempts. Both type I and type II muscle fibers are involved in the disease process. Genetic studies indicate an autosomal recessive mode of inheritance. Although the primary defect in muscular dystrophy is traditionally thought to reside in skeletal muscle, recent studies have produced theories of primary involvement of other tissues and organ systems. These theories are presented and relationships to the traditional theory are discussed.     

Impaired mitochondrial oxidative phosphorylation in skeletal muscle of the dystrophin-deficient mdx mouse

The mdx mouse, an animal model of the Duchenne muscular dystrophy, was used for the investigation of changes in mitochondrial function associated with dystrophin deficiency. Enzymatic analysis of skeletal muscle showed an approximately 50% decrease in the activity of all respiratory chain-linked enzymes in musculus quadriceps of adult mdx mice as compared with controls, while in cardiac muscle no difference was observed. The activities of cytosolic and mitochondrial matrix enzymes were not significantly different from the control values in both cardiac and skeletal muscles. In saponin-permeabilized skeletal muscle fibers of mdx mice the maximal rates of mitochondrial respiration were about two times lower than those of controls. These changes were also demonstrated on the level of isolated mitochondria. Mdx muscle mitochondria had only 60% of maximal respiration activities of control mice skeletal muscle mitochondria and contained only about 60% of hemoproteins of mitochondrial inner membrane. Similar findings were observed in a skeletal muscle biopsy of a Duchenne muscular dystrophy patient. These data strongly suggest that a specific decrease in the amount of all mitochondrial inner membrane enzymes, most probably as result of Ca²⁺ overload of muscle fibers, is the reason for the bioenergetic deficits in dystrophin-deficient skeletal muscle.     

A proprioception based regulation model to estimate the trunk muscle forces

Evaluation of loads acting on the spine requires the knowledge of the muscular forces acting on it, but muscles redundancy necessitates developing a muscle forces attribution strategy. Optimisation, EMG, or hybrid models allow evaluating muscle force patterns, yielding a unique muscular arrangement or/and requiring EMG data collection. This paper presents a regulation model of the trunk muscles based on a proprioception hypothesis, which searches to avoid the spinal joint overloading. The model is also compared to other existing models for evaluation. Compared to an optimisation model, the proposed alternative muscle pattern yielded a significant spine postero-anterior shear decrease. Compared to a model based on combination of optimisation criteria, present model better fits muscle activation observed using EMG (38% improvement). Such results suggest that the proposed model, based on regulation of all spinal components, may be more relevant from a physiologic point of view.     

A Proprioception Based Regulation Model to Estimate the Trunk Muscle Forces

Evaluation of loads acting on the spine requires the knowledge of the muscular forces acting on it, but muscles redundancy necessitates developing a muscle forces attribution strategy. Optimisation, EMG, or hybrid models allow evaluating muscle force patterns, yielding a unique muscular arrangement or/and requiring EMG data collection. This paper presents a regulation model of the trunk muscles based on a proprioception hypothesis, which searches to avoid the spinal joint overloading. The model is also compared to other existing models for evaluation. Compared to an optimisation model, the proposed alternative muscle pattern yielded a significant spine postero-anterior shear decrease. Compared to a model based on combination of optimisation criteria, present model better fits muscle activation observed using EMG (38% improvement). Such results suggest that the proposed model, based on regulation of all spinal components, may be more relevant from a physiologic point of view.     

Optimal length of smooth muscle assessed by a microstructurally and statistically based constitutive model

Smooth muscle exhibits an optimal length at which it is able to generate a maximum amount of force. In this study, the optimal length is assessed by use of a microstructurally and statistically based constitutive model for smooth muscle. The model is based on the sliding filament theory, and a modified version of Hill's mechanical model was adopted. It was conjectured, that a variation in the overlap in the actomyosin contractile units together with a statistical dispersion in the size of the dense bodies are responsible for the optimal length characteristics. The influence of contractile unit length, dense body size and dense body compliance was investigated, and the model was fully able to predict experimental data. The results indicate that the compliance of the dense bodies does not contribute significantly to the total compliance of the contractile apparatus.     

Distinctive Serum miRNA Profile in Mouse Models of Striated Muscular Pathologies

Biomarkers are critically important for disease diagnosis and monitoring. In particular, close monitoring of disease evolution is eminently required for the evaluation of therapeutic treatments. Classical monitoring methods in muscular dystrophies are largely based on histological and molecular analyses of muscle biopsies. Such biopsies are invasive and therefore difficult to obtain. The serum protein creatine kinase is a useful biomarker, which is however not specific for a given pathology and correlates poorly with the severity or course of the muscular pathology. The aim of the present study was the systematic evaluation of serum microRNAs (miRNAs) as biomarkers in striated muscle pathologies. Mouse models for five striated muscle pathologies were investigated: Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy type 2D (LGMD2D), limb-girdle muscular dystrophy type 2C (LGMD2C), Emery-Dreifuss muscular dystrophy (EDMD) and hypertrophic cardiomyopathy (HCM). Two-step RT-qPCR methodology was elaborated, using two different RT-qPCR miRNA quantification technologies. We identified miRNA modulation in the serum of all the five mouse models. The most highly dysregulated serum miRNAs were found to be commonly upregulated in DMD, LGMD2D and LGMD2C mouse models, which all exhibit massive destruction of striated muscle tissues. Some of these miRNAs were down rather than upregulated in the EDMD mice, a model without massive myofiber destruction. The dysregulated miRNAs identified in the HCM model were different, with the exception of one dysregulated miRNA common to all pathologies. Importantly, a specific and distinctive circulating miRNA profile was identified for each studied pathological mouse model. The differential expression of a few dysregulated miRNAs in the DMD mice was further evaluated in DMD patients, providing new candidates of circulating miRNA biomarkers for DMD.     

Role of gastrocnemius-soleus muscle in forefoot force transmission at heel rise - A 3D finite element analysis

The functions of the gastrocnemius-soleus (G-S) complex and other plantar flexor muscles are to stabilize and control major bony joints, as well as to provide primary coordination of the foot during the stance phase of gait. Geometric positioning of the foot and transferring of plantar loads can be adversely affected when muscular control is abnormal (e.g., equinus contracture). Although manipulation of the G-S muscle complex by surgical intervention (e.g., tendo-Achilles lengthening) is believed to be effective in restoring normal plantar load transfer in the foot, there is lack of quantitative data supporting that notion. Thus, the objective of this study is to formulate a three-dimensional musculoskeletal finite element model of the foot to quantify the precise role of the G-S complex in terms of biomechanical response of the foot. The model established corresponds to a muscle-demanding posture during heel rise, with simulated activation of major extrinsic plantar flexors. In the baseline (reference) case, required muscle forces were determined from what would be necessary to generate the targeted resultant ground reaction forces. The predicted plantar load transfer through the forefoot plantar surface, as indicated by plantar pressure distribution, was verified by comparison with experimental observations. This baseline model served as a reference for subsequent parametric analysis, where muscle forces applied by the G-S complex were decreased in a step-wise manner. Adaptive changes of the foot mechanism, in terms of internal joint configurations and plantar stress distributions, in response to altered muscular loads were analyzed. Movements of the ankle and metatarsophalangeal joints, as well as forefoot plantar pressure peaks and pressure distribution under the metatarsal heads (MTHs), were all found to be extremely sensitive to reduction in the muscle load in the G-S complex. A 40% reduction in G-S muscle stabilization can result in dorsal-directed rotations of 8.81° at the ankle, and a decreased metatarsophalangeal joint extension of 4.65°. The resulting peak pressure reductions at individual MTHs, however, may be site-specific and possibly dependent on foot structure, such as intrinsic alignment of the metatarsals. The relationships between muscular control, internal joint movements, and plantar load distributions are envisaged to have important clinical implications on tendo-Achilles lengthening procedures, and to provide surgeons with an understanding of the underlying mechanism for relieving forefoot pressure in diabetic patients suffering from ankle equinus contracture.     

Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector

Limb-girdle muscular dystrophies 2C-F represent a family of autosomal recessive diseases caused by defects in sarcoglycan genes. The cardiomyopathic hamster is a naturally occurring model for limb-girdle muscular dystrophy caused by a primary deficiency in delta-sarcoglycan. We show here that acute sarcolemmal disruption occurs in this animal model during forceful muscle contraction. A recombinant adeno-associated virus vector encoding human delta-sarcoglycan conferred efficient and stable genetic reconstitution in the adult cardiomyopathic hamster when injected directly into muscle. A quantitative assay demonstrated that vector-transduced muscle fibers are stably protected from sarcolemmal disruption; there was no associated inflammation or immunologic response to the vector-encoded protein. Efficient gene transduction with rescue of the sarcoglycan complex in muscle fibers of the distal hindlimb was also obtained after infusion of recombinant adeno-associated virus into the femoral artery in conjunction with histamine-induced endothelial permeabilization. This study provides a strong rationale for the development of gene therapy for limb-girdle muscular dystrophy.     

An optimal control model for maximum-height human jumping

To understand how intermuscular control, inertial interactions among body segments, and musculotendon dynamics coordinate human movement, we have chosen to study maximum-height jumping. Because this activity presents a relatively unambiguous performance criterion, it fits well into the framework of optimal control theory. The human body is modeled as a four-segment, planar, articulated linkage, with adjacent links joined together by frictionless revolutes. Driving the skeletal system are eight musculotendon actuators, each muscle modeled as a three-element, lumped-parameter entity, in series with tendon. Tendon is assumed to be elastic, and its properties are defined by a stress-strain curve. The mechanical behavior of muscle is described by a Hill-type contractile element, including both series and parallel elasticity. Driving the musculotendon model is a first-order representation of excitation-contraction (activation) dynamics. The optimal control problem is to maximize the height reached by the center of mass of the body subject to body-segmental, musculotendon, and activation dynamics, a zero vertical ground reaction force at lift-off, and constraints which limit the magnitude of the incoming neural control signals to lie between zero (no excitation) and one (full excitation). A computational solution to this problem was found on the basis of a Mayne-Polak dynamic optimization algorithm. Qualitative comparisons between the predictions of the model and previously reported experimental findings indicate that the model reproduces the major features of a maximum-height squat jump (i.e. limb-segmental angular displacements, vertical and horizontal ground reaction forces, sequence of muscular activity, overall jump height, and final lift-off time).     

Dystrophin is required for the formation of stable muscle attachments in the zebrafish embryo

A class of recessive lethal zebrafish mutations has been identified in which normal skeletal muscle differentiation is followed by a tissue-specific degeneration that is reminiscent of the human muscular dystrophies. Here, we show that one of these mutations, sapje, disrupts the zebrafish orthologue of the X-linked human Duchenne muscular dystrophy (DMD) gene. Mutations in this locus cause Duchenne or Becker muscular dystrophies in human patients and are thought to result in a dystrophic pathology through disconnecting the cytoskeleton from the extracellular matrix in skeletal muscle by reducing the level of dystrophin protein at the sarcolemma. This is thought to allow tearing of this membrane, which in turn leads to cell death. Surprisingly, we have found that the progressive muscle degeneration phenotype of sapje mutant zebrafish embryos is caused by the failure of embryonic muscle end attachments. Although a role for dystrophin in maintaining vertebrate myotendinous junctions (MTJs) has been postulated previously and MTJ structural abnormalities have been identified in the Dystrophin-deficient mdx mouse model, in vivo evidence of pathology based on muscle attachment failure has thus far been lacking. This zebrafish mutation may therefore provide a model for a novel pathological mechanism of Duchenne muscular dystrophy and other muscle diseases.     

Zebrafish models flex their muscles to shed light on muscular dystrophies

Muscular dystrophies are a group of genetic disorders that specifically affect skeletal muscle and are characterized by progressive muscle degeneration and weakening. To develop therapies and treatments for these diseases, a better understanding of the molecular basis of muscular dystrophies is required. Thus, identification of causative genes mutated in specific disorders and the study of relevant animal models are imperative. Zebrafish genetic models of human muscle disorders often closely resemble disease pathogenesis, and the optical clarity of zebrafish embryos and larvae enables visualization of dynamic molecular processes in vivo. As an adjunct tool, morpholino studies provide insight into the molecular function of genes and allow rapid assessment of candidate genes for human muscular dystrophies. This unique set of attributes makes the zebrafish model system particularly valuable for the study of muscle diseases. This review discusses how recent research using zebrafish has shed light on the pathological basis of muscular dystrophies, with particular focus on the muscle cell membrane and the linkage between the myofibre cytoskeleton and the extracellular matrix.