Addition Of Sarcomeres In Series Research Articles

Age-related blunting of serial sarcomerogenesis and mechanical adaptations following 4 wk of maximal eccentric resistance training.

During aging, muscles undergo atrophy, which is partly accounted for by a loss of sarcomeres in series. Serial sarcomere number (SSN) is associated with aspects of muscle mechanical function including the force-length and force-velocity-power relationships; hence, the age-related loss of SSN contributes to declining performance. Training emphasizing eccentric contractions increases SSN in young healthy rodents; however, the ability for eccentric training to increase SSN in old age is unknown. Ten young (8 mo) and 11 old (32 mo) male Fisher344/BN rats completed 4 wk of unilateral eccentric plantar flexion training. Pre- and posttraining, the plantar flexors were assessed for the torque-frequency, passive torque-angle, and torque-velocity-power relationships. The soleus, lateral gastrocnemius (LG), and medial gastrocnemius (MG) were harvested for SSN assessment via laser diffraction, with the untrained leg used as a control. In the untrained leg/pretraining, old rats had lower SSN in the soleus, LG, and MG, lower maximum torque, power, and shortening velocity, and greater passive torque than young. Young showed increased soleus and MG SSN following training. In contrast, old had no change in soleus SSN and experienced SSN loss in the LG. Pre- to posttraining, young experienced an increase in maximum isometric torque, whereas old had reductions in maximum torque, shortening velocity, and power, and increased passive torque. Our results show that although young muscle has the ability to add sarcomeres in response to maximal eccentric training, this stimulus could be not only ineffective, but also detrimental to aged muscle leading to dysfunctional remodeling.NEW & NOTEWORTHY The loss of sarcomeres in series with age contributes to declining muscle performance. The present study investigated whether eccentric training could improve performance via serial sarcomere addition in old muscle, like in young muscle. Four weeks of maximal eccentric training induced serial sarcomere addition in the young rat plantar flexors and improved in vivo performance, however, led to dysfunctional remodeling accompanied by further impaired performance in old rats.

The importance of serial sarcomere addition for muscle function and the impact of aging.

During natural aging, skeletal muscle experiences impairments in mechanical performance due, in part, to changes in muscle architecture and size, notably with a loss of muscle cross-sectional area. Another important factor that has received less attention is the shortening of fascicle length, potentially reflective of a decrease in serial sarcomere number (SSN). Interventions that promote the growth of new serial sarcomeres, such as chronic stretching and eccentric-biased resistance training, have been suggested as potential ways to mitigate age-related impairments in muscle function. While current research suggests it is possible to stimulate serial sarcomerogenesis in muscle in old age, the magnitude of sarcomerogenesis may be less than in young muscle. This blunted effect may be partly due to age-related impairments in the pathways regulating mechanotransduction, muscle gene expression, and protein synthesis, as some have been implicated in SSN adaptation. The purpose of this review was to investigate the impact of aging on the ability for serial sarcomerogenesis, and elucidate the molecular pathways that may limit serial sarcomerogenesis in old age. Age-related changes in mTOR, IGF-1, myostatin, and serum response factor signalling, MuRFs, and satellite cells may hinder serial sarcomerogenesis. In addition, our current understanding of SSN in older humans is limited by assumptions based on ultrasound-derived fascicle length. Future research should explore the effects of age-related changes in the identified pathways on the ability to stimulate serial sarcomerogenesis, and better estimate SSN adaptations to gain a deeper understanding of the adaptability of muscle in old age.

Stimuli for Adaptations in Muscle Length and the Length Range of Active Force Exertion-A Narrative Review.

Treatment strategies and training regimens, which induce longitudinal muscle growth and increase the muscles’ length range of active force exertion, are important to improve muscle function and to reduce muscle strain injuries in clinical populations and in athletes with limited muscle extensibility. Animal studies have shown several specific loading strategies resulting in longitudinal muscle fiber growth by addition of sarcomeres in series. Currently, such strategies are also applied to humans in order to induce similar adaptations. However, there is no clear scientific evidence that specific strategies result in longitudinal growth of human muscles. Therefore, the question remains what triggers longitudinal muscle growth in humans. The aim of this review was to identify strategies that induce longitudinal human muscle growth. For this purpose, literature was reviewed and summarized with regard to the following topics: (1) Key determinants of typical muscle length and the length range of active force exertion; (2) Information on typical muscle growth and the effects of mechanical loading on growth and adaptation of muscle and tendinous tissues in healthy animals and humans; (3) The current knowledge and research gaps on the regulation of longitudinal muscle growth; and (4) Potential strategies to induce longitudinal muscle growth. The following potential strategies and important aspects that may positively affect longitudinal muscle growth were deduced: (1) Muscle length at which the loading is performed seems to be decisive, i.e., greater elongations after active or passive mechanical loading at long muscle length are expected; (2) Concentric, isometric and eccentric exercises may induce longitudinal muscle growth by stimulating different muscular adaptations (i.e., increases in fiber cross-sectional area and/or fiber length). Mechanical loading intensity also plays an important role. All three training strategies may increase tendon stiffness, but whether and how these changes may influence muscle growth remains to be elucidated. (3) The approach to combine stretching with activation seems promising (e.g., static stretching and electrical stimulation, loaded inter-set stretching) and warrants further research. Finally, our work shows the need for detailed investigation of the mechanisms of growth of pennate muscles, as those may longitudinally grow by both trophy and addition of sarcomeres in series.

Biceps femoris long head sarcomere and fascicle length adaptations after 3 weeks of eccentric exercise training

BackgroundEccentric exercise increases muscle fascicle lengths; however, the mechanisms behind this adaptation are still unknown. This study aimed to determine whether biceps femoris long head (BFlh) fascicle length increases in response to 3 weeks of eccentric exercise training are the result of an in-series addition of sarcomeres within the muscle fibers. MethodsTen recreationally active participants (age = 27 ± 3 years; mass = 70 ± 14 kg; height = 174 ± 9 cm; mean ± SD) completed 3 weeks of Nordic hamstring exercise (NHE) training on a custom exercise device that was instrumented with load cells. We collected in vivo sarcomere and muscle fascicle images of the BFlh in 2 regions (central and distal) by using microendoscopy and 3 dimension ultrasonography. We then estimated sarcomere length, sarcomere number, and fascicle length before and after the training intervention. ResultsEccentric knee flexion strength increased after the training (15%; p < 0.001; ηp2 = 0.75). Further, we found a significant increase in fascicle length (21%; p < 0.001; ηp2 = 0.81) and sarcomere length (17%; p < 0.001; ηp2 = 0.90) in the distal but not in the central portion of the muscle. The estimated number of sarcomeres in series did not change in either region. ConclusionFascicle length adaptations appear to be heterogeneous in the BFlh in response to 3 weeks of NHE training. An increase in sarcomere length, rather than the addition of sarcomeres in series, appears to underlie increases in fascicle length in the distal region of the BFlh. The mechanism driving regional increases in fascicle and sarcomere length remains unknown, but we speculate that it may be driven by regional changes in the passive tension of muscle or connective tissue adaptations.

Multiscale characterization of heart failure

Dilated cardiomyopathy is a progressive irreversible disease associated with contractile dysfunction and heart failure. During dilated cardiomyopathy, elevated diastolic wall strains trigger mechanotransduction pathways that initiate the addition of sarcomeres in series and an overall increase in myocyte length. At the whole organ level, this results in a chronic dilation of the ventricles, an increase in end diastolic and end systolic volumes, and a decrease in ejection fraction. However, how exactly changes in sarcomere number translate into changes in myocyte morphology, and how these cellular changes translate into ventricular dilation remains incompletely understood. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. In an eight-week long volume overload study of six pigs, we found that the average sarcomere number increased by +3.8%/week, from 47 to 62, resulting in a myocyte lengthening of +3.3%/week, from 85 to 108 μm, while the sarcomere length and myocyte width remained unchanged. At the same time, the average end diastolic volume increased by +6.0%/week. Using continuum growth modeling and Bayesian inference, we correlated alterations on the subcellular, cellular, and organ scales and found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results demonstrate that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. We anticipate our study to be a starting point for more sophisticated multiscale models of heart failure. Our study suggests that altering sarcomere turnover-and with it myocyte morphology and ventricular dimensions-could be a potential therapeutic target to attenuate or reverse the progression of heart failure. Statement of SignificanceHeart failure is a significant global health problem that affects more than 25 million people worldwide and increases in prevalence as the population ages. Heart failure has been studied excessively at various scales; yet, there is no compelling concept to connect knowledge from the subcellular, cellular, and organ level across the scales. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. We found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results show that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. This suggests that altering the sarcomere turnover—and with it myocyte morphology and ventricular dimensions–could be a potential therapeutic target to attenuate or reverse heart failure.

Multiscale Characterization of Heart Failure

Dilated cardiomyopathy is a progressive irreversible disease associated with contractile dysfunction and heart failure. During dilated cardiomyopathy, elevated diastolic wall strains trigger mechanotransduction pathways that initiate the addition of sarcomeres in series and an overall increase in myocyte length. At the whole organ level, this results in a chronic dilation of the ventricles, an increase in end diastolic and end systolic volumes, and a decrease in ejection fraction. However, how exactly changes in sarcomere number translate into changes in myocyte morphology, and how these cellular changes translate into ventricular dilation remains incompletely understood. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. In an eight-week long volume overload study of n=6 pigs, we found that the average sarcomere number increased by 3.8%/week, from 47 to 62, resulting in a myocyte lengthening of 3.3%/week, from 85 to 108um, while the sarcomere length and myocyte width remained unchanged. At the same time, the average end diastolic volume increased by 6.0%/week. Using continuum growth modeling and Bayesian inference, we correlated alterations on the subcellular, cellular, and organ scales and found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results demonstrate that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. We anticipate our study to be a starting point for more sophisticated multiscale models of heart failure. Our study suggests that altering sarcomere turnover -- and with it myocyte morphology and ventricular dimensions -- could be a potential therapeutic target to attenuate or reverse the progression of heart failure.

Reduced skeletal muscle satellite cell number alters muscle morphology after chronic stretch but allows limited serial sarcomere addition

Muscles add sarcomeres in response to stretch, presumably to maintain optimal sarcomere length. Clinical evidence from patients with cerebral palsy, who have both decreased serial sarcomere number and reduced satellite cells (SCs), suggests a hypothesis that SCs may be involved in sarcomere addition. A transgenic Pax7-DTA mouse model underwent conditional SC depletion, and their soleii were then stretch-immobilized to assess the capacity for sarcomere addition. Muscle architecture, morphology, and extracellular matrix (ECM) changes were also evaluated. Mice in the SC-reduced group achieved normal serial sarcomere addition in response to stretch. However, muscle fiber cross-sectional area was significantly smaller and was associated with hypertrophic ECM changes, consistent with fibrosis. While a reduced SC population does not hinder serial sarcomere addition, SCs play a role in muscle adaptation to chronic stretch that involves maintenance of both fiber cross-sectional area and ECM structure. Muscle Nerve 55: 384-392, 2017.

Chronic Adaptations to Eccentric Training: A Systematic Review.

Resistance training is an integral component of physical preparation for athletes. A growing body of evidence indicates that eccentric strength training methods induce novel stimuli for neuromuscular adaptations. The purpose of this systematic review was to determine the effects of eccentric training in comparison to concentric-only or traditional (i.e. constrained by concentric strength) resistance training. Searches were performed using the electronic databases MEDLINE via EBSCO, PubMed and SPORTDiscus via EBSCO. Full journal articles investigating the long-term (≥4weeks) effects of eccentric training in healthy (absence of injury or illness during the 4weeks preceding the training intervention), adult (17-35years), human participants were selected for the systematic review. A total of 40 studies conformed to these criteria. Eccentric training elicits greater improvements in muscle strength, although in a largely mode-specific manner. Superior enhancements in power and stretch-shortening cycle (SSC) function have also been reported. Eccentric training is at least as effective as other modalities in increasing muscle cross-sectional area (CSA), while the pattern of hypertrophy appears nuanced and increased CSA may occur longitudinally within muscle (i.e. the addition of sarcomeres in series). There appears to be a preferential increase in the size of type II muscle fibres and the potential to exert a unique effect upon fibre type transitions. Qualitative and quantitative changes in tendon tissue that may be related to the magnitude of strain imposed have also been reported with eccentric training. Eccentric training is a potent stimulus for enhancements in muscle mechanical function, and muscle-tendon unit (MTU) morphological and architectural adaptations. The inclusion of eccentric loads not constrained by concentric strength appears to be superior to traditional resistance training in improving variables associated with strength, power and speed performance.

Fascicle length does increase in response to longitudinal resistance training and in a contraction-mode specific manner.

Fascicle length does increase in response to longitudinal resistance training and in a contraction-mode specific manner.

Muscle structural assembly and functional consequences.

The relationship between muscle structure and function has been a matter of investigation since the Renaissance period. Extensive use of anatomical dissections and the introduction of the scientific method enabled early scholars to lay the foundations of muscle physiology and biomechanics. Progression of knowledge in these disciplines led to the current understanding that muscle architecture, together with muscle fibre contractile properties, has a major influence on muscle mechanical properties. Recently, advances in laser diffraction, optical microendoscopy and ultrasonography have enabled in vivo investigations into the behaviour of human muscle fascicles and sarcomeres with varying joint angle and muscle contraction intensity. With these technologies it has become possible to identify the length region over which fascicles and sarcomeres develop maximum isometric force in vivo as well as the operating ranges of fascicles and sarcomeres during real-life activities such as walking. Also, greater insights into the remodelling of muscle architecture in response to overloading and unloading, and in ageing, have been obtained by the use of ultrasonography; these have led to the identification of clinical biomarkers of disuse atrophy and sarcopenia. Recent evidence also shows that the pattern of muscle hypertrophy in response to chronic loading is contraction-mode dependent (eccentric versus concentric), as similar gains in muscle mass, but through differing addition of sarcomeres in series and in parallel (as indirectly inferred from changes in fascicle length and pennation angle), have been found. These innovative observations prompted a new set of investigations into the molecular mechanisms regulating this contraction-specific muscle growth.

Different Molecular and Structural Adaptations with Eccentric and Conventional Strength Training in Elderly Men and Women

Reprogramming of gene expression contributes to structural and functional adaptation of muscle tissue in response to altered use. The aim of this study was to investigate mechanisms for observed improvements in leg extension strength, gain in relative thigh muscle mass and loss of body and thigh fat content in response to eccentric and conventional strength training in elderly men (n = 14) and women (n = 14; average age of the men and women: 80.1 ± 3.7 years) by means of structural and molecular analyses. Biopsies were collected from m. vastus lateralis in the resting state before and after 12 weeks of training with two weekly resistance exercise sessions (RET) or eccentric ergometer sessions (EET). Gene expression was analyzed using custom-designed low-density PCR arrays. Muscle ultrastructure was evaluated using EM morphometry. Gain in thigh muscle mass was paralleled by an increase in muscle fiber cross-sectional area (hypertrophy) with RET but not with EET, where muscle growth is likely occurring by the addition of sarcomeres in series or by hyperplasia. The expression of transcripts encoding factors involved in muscle growth, repair and remodeling (e.g. IGF-1, HGF, MYOG, MYH3) was increased to a larger extent after EET than RET. MicroRNA 1 expression was decreased independent of the training modality, and was paralleled by an increased expression of IGF-1 representing a potential target. IGF-1 is a potent promoter of muscle growth, and its regulation by microRNA 1 may have contributed to the gain of muscle mass observed in our subjects. EET depressed genes encoding mitochondrial and metabolic transcripts. The changes of several metabolic and mitochondrial transcripts correlated significantly with changes in mitochondrial volume density. Intramyocellular lipid content was decreased after EET concomitantly with total body fat. Changes in intramyocellular lipid content correlated with changes in body fat content with both RET and EET. In the elderly, RET and EET lead to distinct molecular and structural adaptations which might contribute to the observed small quantitative differences in functional tests and body composition parameters. EET seems to be particularly convenient for the elderly with regard to improvements in body composition and strength but at the expense of reducing muscular oxidative capacity.

Extracellular Signal-Regulated Kinases 1 and 2 Regulate the Balance Between Eccentric and Concentric Cardiac Growth

An increase in cardiac afterload typically produces concentric hypertrophy characterized by an increase in cardiomyocyte width, whereas volume overload or exercise results in eccentric growth characterized by cellular elongation and addition of sarcomeres in series. The signaling pathways that control eccentric versus concentric heart growth are not well understood. To determine the role of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in regulating the cardiac hypertrophic response. Here, we used mice lacking all ERK1/2 protein in the heart (Erk1(-/-) Erk2(fl/fl-Cre)) and mice expressing activated mitogen-activated protein kinase kinase (Mek)1 in the heart to induce ERK1/2 signaling, as well as mechanistic experiments in cultured myocytes to assess cellular growth characteristics associated with this signaling pathway. Although genetic deletion of all ERK1/2 from the mouse heart did not block the cardiac hypertrophic response per se, meaning that the heart still increased in weight with both aging and pathological stress stimulation, it did dramatically alter how the heart grew. For example, adult myocytes from hearts of Erk1(-/-) Erk2(fl/fl-Cre) mice showed preferential eccentric growth (lengthening), whereas myocytes from Mek1 transgenic hearts showed concentric growth (width increase). Isolated adult myocytes acutely inhibited for ERK1/2 signaling by adenoviral gene transfer showed spontaneous lengthening, whereas infection with an activated Mek1 adenovirus promoted constitutive ERK1/2 signaling and increased myocyte thickness. A similar effect was observed in engineered heart tissue under cyclic stretching, where ERK1/2 inhibition led to preferential lengthening. Taken together, these data demonstrate that the ERK1/2 signaling pathway uniquely regulates the balance between eccentric and concentric growth of the heart.

A multiscale model for eccentric and concentric cardiac growth through sarcomerogenesis

We present a novel computational model for maladaptive cardiac growth in which kinematic changes of the cardiac chambers are attributed to alterations in cytoskeletal architecture and in cellular morphology. We adopt the concept of finite volume growth characterized through the multiplicative decomposition of the deformation gradient into an elastic part and a growth part. The functional form of its growth tensor is correlated to sarcomerogenesis, the creation and deposition of new sarcomere units. In response to chronic volume-overload, an increased diastolic wall strain leads to the addition of sarcomeres in series, resulting in a relative increase in cardiomyocyte length, associated with eccentric hypertrophy and ventricular dilation. In response to chronic pressure-overload, an increased systolic wall stress leads to the addition of sacromeres in parallel, resulting in a relative increase in myocyte cross sectional area, associated with concentric hypertrophy and ventricular wall thickening. The continuum equations for both forms of maladaptive growth are discretized in space using a nonlinear finite element approach, and discretized in time using the implicit Euler backward scheme. We explore a generic bi-ventricular heart model in response to volume- and pressure-overload to demonstrate how local changes in cellular morphology translate into global alterations in cardiac form and function.

Immobilization of the rabbit tibialis anterior muscle in a lengthened position causes addition of sarcomeres in series and extra-cellular matrix proliferation

Rabbits were immobilized for 3 weeks with the ankle in plantar flexion, midrange position or dorsal extension (n=15). The left leg was used as control. Sarcomere lengths were measured by laser diffraction in vivo in the tibialis anterior (TA) muscle. Legs immobilized in the midrange position showed coherent diffraction patterns through the range of motion, but in those immobilized with TA in the stretched position no diffraction patterns in vivo could be obtained. Morphological analyses revealed increased fibrosis and occurrence of whorled fibers in these muscles. On 15 more likewise immobilized rabbits, a technique of measuring sarcomere lengths in vitro by first digesting the collagen in nitric acid was developed. These in vitro measurements showed shorter sarcomeres in the muscles immobilized in a lengthened position compared to the control, indicating an addition of sarcomeres in series.

CASE REPORT: Muscle Adaptation by Serial Sarcomere Addition 1 Year after Femoral Lengthening

A common complication of reconstructive surgery is muscle contracture and consequent loss of joint motion. This particularly occurs in surgical lengthening procedures where the muscle adaptive capacity seems to limit the extent of possible lengthening. We used intraoperative laser diffraction to determine the skeletal muscle adaptation that occurred in a 16-year-old girl who had 4-cm femoral lengthening for a leg-length discrepancy secondary to posttraumatic growth arrest. Fascicle length changed dramatically during distraction from a starting value of approximately 9 cm to a new length of 19 cm. In vivo vastus lateralis sarcomere length measured intraoperatively at the initial surgery was 3.64 microm, whereas sarcomere length measured 8 months later was 3.11 microm. The fact that fascicle length increased dramatically and in vivo sarcomere length decreased slightly reveals an increase in serial sarcomeres from 25,000 to 58,650. This direct measurement of fascicle length and sarcomere length confirms sarcomerogenesis in human skeletal muscle secondary to chronic length change, and shows the capacity of human muscle to adapt to length changes.

Sarcomeric Alpha‐actinin is a Myotendinous Junction Component in Neonatal Mice

Myotendinous junctions (MTJs) are cell adhesion sites where new sarcomeres are added in series during longitudinal muscle growth. Currently, little is known about the developmental dynamics of this specialized region of the muscle cell. This study compared the ultrastructure and composition of MTJs from rapidly-growing neonatal mice, and adult mice whose muscles have reached a steady-state length. At neonatal MTJs membrane exhibits greatly reduced folding, myofibrils are immature and interspersed with unorganized cytoplasm, and the tendon is densely populated with mononucleated cells, most likely fibroblasts, many of which are in close association with the muscle cell. Immunolocalization of the nebulin-related protein N-RAP, which is localized exclusively to the terminal cytoskeletal filament bundles at MTJs in adult skeletal muscle, is also restricted to these sites in neonatal muscle. Vinculin and dystrophin were co-localized subjacent to the membrane, also at both adult and neonatal MTJs. Interestingly, sarcomeric α-actinin was localized to MTJ adhesion plaques in neonates, but was not detected at the adult MTJ. The variable presence of sarcomeric α-actinin at MTJs suggests that muscle fibers differentially regulate actin-membrane interactions during postnatal growth, either in response to developmental stage-specific differences in mechanical stress, or to accommodate serial sarcomere addition in neonates. Supported by a grant from the American Heart Association, and by the Dean of the UMKC School of Biological Sciences.

Differential serial sarcomere number adaptations in knee extensor muscles of rats is contraction type dependent

Sarcomerogenesis, or the addition of sarcomeres in series within a fiber, has a profound impact on the performance of a muscle by increasing its contractile velocity and power. Sarcomerogenesis may provide a beneficial adaptation to prevent injury when a muscle consistently works at long lengths, accounting for the repeated-bout effect. The association between eccentric exercise, sarcomerogenesis and the repeated-bout effect has been proposed to depend on damage, where regeneration allows sarcomeres to work at shorter lengths for a given muscle-tendon unit length. To gain additional insight into this phenomenon, we measured fiber dynamics directly in the vastus lateralis (VL) muscle of rats during uphill and downhill walking, and we measured serial sarcomere number in the VL and vastus intermedius (VI) after chronic training on either a decline or incline grade. We found that the knee extensor muscles of uphill walking rats undergo repeated active concentric contractions, and therefore they suffer no contraction-induced injury. Conversely, the knee extensor muscles during downhill walking undergo repeated active eccentric contractions. Serial sarcomere numbers change differently for the uphill and downhill exercise groups, and for the VL and VI muscles. Short muscle lengths for uphill concentric-biased contractions result in a loss of serial sarcomeres, and long muscle lengths for downhill eccentric-biased contractions result in a gain of serial sarcomeres.

Lengthening of muscle during distraction osteogenesis.

Chronic lengthening of immobilized, neurally intact muscle leads to the addition of sarcomeres in series. Confirmation of a similar adaptation during distraction osteogenesis is crucial for providing a rationale for a successful outcome of the intervention. When distraction osteogenesis (at < or = 1.4 mm/day) is done in skeletally immature animals, muscle adapts by creating a longer and functionally intact muscle. This is achieved through muscle growth, the proliferation of myogenic cells ultimately leading to serial addition of sarcomeres. When distraction osteogenesis is done in skeletally mature animals, however, the same distraction regimen leads to a lengthened muscle that has significant fibrosis and weakness, the latter possibly a result of partial denervation. Despite a modest but significant elevation of local insulinlike growth factor-1 in the lengthened muscles from adult animals, muscle growth is not adequate and leads to a loss of function. In adult animals, the distraction osteogenesis-induced increase in insulinlike growth factor-1 is insufficient to facilitate muscle growth during lengthening. Muscle can be targeted for future therapeutic use of insulinlike growth factor-1; however, such a therapy also may lead to increased fibrosis.

The effect of the amount of limb lengthening on skeletal muscle.

The adaptation of tibialis anterior muscles after 20% and 30% gradual limb lengthening was evaluated. Eight skeletally mature neutered male goats had 20% (n = 4) or 30% (n = 4) tibial distraction at a rate of 0.25 mm three times per day. Muscles from lengthened and contralateral control limbs were harvested on completion of distraction. Fiber length and sarcomere length were measured followed by calculation of sarcomere number and muscle fiber-to-bone lengthening ratio. Fiber length and sarcomere number after 20% and 30% limb lengthening were significantly greater in the distracted muscles, whereas no difference in sarcomere length was detected. The difference in muscle fiber length and sarcomere number between distracted and control limbs was greater in the 30% than in the 20% group. The disproportion between the amounts of muscle fiber and bone length increase was similar after 20% and 30% lengthening. The results show that muscular adaptation continues during 20% to 30% limb lengthening by increasing fiber length. It seems that this increase occurs through serial sarcomere addition rather than sarcomere length alteration. The higher rate of musclerelated clinical complications after limb lengthening beyond 20% does not seem to be related to a failure of muscle fiber contractile elements to adapt to increasing limb length.

Tratamiento de la espasticidad en parálisis cerebral con toxina botulínica

A review of the pathophysiological and developmental basis, measurement scales and the usefulness of botulinum toxin A injections in selected muscles for the treatment of spasticity in children with cerebral palsy.Cerebral palsy is the most common cause of spasticity in children. The increase in muscle length is achieved through the addition of sarcomeres in series at the level of the muscle tendinous junction. The regulation of the number of sarcomeres seems to be determined by the lengthening of the muscle. The muscle contracture is a shortening of the length of a muscle as a result of a decrease in the number of sarcomeres. Spasticity and motor function assessment scales used in children with cerebral palsy: a) Modified Ashworth scale for the assessment of spasticity; b) modified Tardieu scale for the assessment of dynamic muscle length; c) muscle spasms frequency scale; d) modified Medical Research Council scale for muscle strength; e) hip adductor muscle tone scale; f) global pain scale with affective facial expression represented in a drawing; g) goniometric measurement of the joint range of movement; h) Palisano gross motor function measure; i) observational video gait analysis scale. Recommended guidelines for dosing the botulinum toxin A: 1. Total maximum dose administered per visit up to 15 U/kg or a total of 400 U; 2. Dose range of large muscles 3 to 6 U/kg per visit; 3. Dose range of small muscles 1 to 3 U/kg per visit; 4. Maximum dose per injection site: 50 U dividing the total planned unit dose/muscle into equal amounts/injection site; 5. Frequency: no more than one injection every 3 months, frequently once every 6 or more months.Botulinum toxin A injection is a well tolerated, safe and effective procedure in the treatment of children with spastic cerebral palsy.