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A Coupled Mechanobiological Model of Muscle Regeneration In Cerebral Palsy

ABSTRACT: Cerebral palsy is a neuromusculoskeletal disorder associated with muscle weakness, altered muscle architecture, and progressive musculoskeletal symptoms that worsen with age. Pathological changes at the level of the whole muscle have been shown; however, it is unclear why this progression of muscle impairment occurs at the cellular level. The process of muscle regeneration is complex, and the interactions between cells in the muscle milieu should be considered in the context of cerebral palsy. In this work, we built a coupled mechanobiological model of muscle damage and regeneration to explore the process of muscle regeneration in typical and cerebral palsy conditions, and whether a reduced number of satellite cells in the cerebral palsy muscle environment could cause the muscle regeneration cycle to lead to progressive degeneration of muscle. The coupled model consisted of a finite element model of a muscle fiber bundle undergoing eccentric contraction, and an agent-based model of muscle regeneration incorporating satellite cells, inflammatory cells, muscle fibers, extracellular matrix, fibroblasts, and secreted cytokines. Our coupled model simulated damage from eccentric contraction followed by 28 days of regeneration within the muscle. We simulated cyclic damage and regeneration for both cerebral palsy and typically developing muscle milieus. Here we show the nonlinear effects of altered satellite cell numbers on muscle regeneration, where muscle repair is relatively insensitive to satellite cell concentration above a threshold, but relatively sensitive below that threshold. With the coupled model, we show that the fiber bundle geometry undergoes atrophy and fibrosis with too few satellite cells and excess extracellular matrix, representative of the progression of cerebral palsy in muscle. This work uses in silico modeling to demonstrate how muscle degeneration in cerebral palsy may arise from the process of cellular regeneration and a reduced number of satellite cells.

SUBMITTER: Khuu S

PROVIDER: S-EPMC8429491 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cerebral palsy is primarily an upper motor neuron disease that results in a spectrum of progressive movement disorders. Secondary to the neurological lesion, muscles from patients with cerebral palsy are often spastic and form debilitating contractures that limit range of motion and joint function. With no genetic component, the pathology of skeletal muscle in cerebral palsy is a response to aberrant neurological input in ways that are not fully understood. This study was designed to gain further understanding of the skeletal muscle response to cerebral palsy using microarrays and correlating the transcriptional data with functional measures. Hamstring biopsies from gracilis and semitendinosus muscles were obtained from a cohort of patients with cerebral palsy (n=10) and typically developing patients (n=10) undergoing surgery. Affymetrix HG-U133A 2.0 chips (n=40) were used and expression data was verified for 6 transcripts using quantitative real-time PCR, as well as for two genes not on the microarray. Chips were clustered based on their expression and those from patients with cerebral palsy clustered separately. Significant genes were determined conservatively based on the overlap of three summarization algorithms (n=1,398). Significantly altered genes were analyzed for over-representation among gene ontologies, transcription factors, pathways, microRNA and muscle specific networks. These results centered on an increase in extracellular matrix expression in cerebral palsy as well as a decrease in metabolism and ubiquitin ligase activity. The increase in extracellular matrix products was correlated with mechanical measures demonstrating the importance in disability. These data lay a framework for further studies and novel therapies. Skeletal muscle biopsies from both the gracilis and semitendinosus were obtained during surgery for 20 pediatric subjects for affymetrix microarray analysis. We obtained a group of 10 patients undergoing medial hamstring lengthening in the cerebral palsy group and 10 patients undergoing ACL reconstruction with hamstring autograft in the control group. This provided 40 microarrays in 4 groups to analyze the effect of cerebral palsy and also differences between muscles.

Project description:Muscle spasticity is characterized by exaggerated stretch reflexes and affects about 85% of the children with cerebral palsy. However, the mechanisms underlying spasticity and its influence on gait are not well understood. Here, we first aimed to model the response of spastic hamstrings and gastrocnemii in children with cerebral palsy to fast passive stretches. Then, we evaluated how the model applied to gait. We developed three models based on exaggerated proprioceptive feedback. The first model relied on feedback from muscle fiber length and velocity (velocity-related model), the second model relied on feedback from muscle fiber length, velocity, and acceleration (acceleration-related model), and the third model relied on feedback from muscle force and its first time derivative (force-related model). The force-related model better reproduced measured hamstrings and gastrocnemii activity during fast passive stretches (coefficients of determination (R2): 0.73 ± 0.10 and 0.60 ± 0.13, respectively, and root mean square errors (RMSE): 0.034 ± 0.031 and 0.009 ± 0.007, respectively) than the velocity-related model (R2: 0.46 ± 0.15 and 0.07 ± 0.13, and RMSE: 0.053 ± 0.051 and 0.015 ± 0.009), and the acceleration-related model (R2: 0.47 ± 0.15 and 0.09 ± 0.14, and RMSE: 0.052 ± 0.050 and 0.015 ± 0.008). Additionally, the force-related model predicted hamstrings and gastrocnemii activity that better correlated with measured activity during gait (cross correlations: 0.82 ± 0.09 and 0.85 ± 0.06, respectively) than the activity predicted by the velocity-related model (cross correlations: 0.49 ± 0.17 and 0.71 ± 0.22) and the acceleration-related model (cross correlations: 0.51 ± 0.16 and 0.67 ± 0.20). Our results therefore suggest that force encoding in muscle spindles in combination with altered feedback gains and thresholds underlie activity of spastic muscles during passive stretches and gait. Our model of spasticity opens new perspectives for studying movement impairments due to spasticity through simulation.

Project description:Muscle weakness is a common clinical symptom in children with spastic cerebral palsy (SCP). It is caused by impaired neural ability and altered intrinsic capacity of the muscles. To define the contribution of decreased muscle size to muscle weakness, two cohorts were recruited in this cross-sectional investigation: 53 children with SCP [median age, 8.2 (IQR, 4.1) years, 19/34 uni/bilateral] and 31 children with a typical development (TD) [median age, 9.7 (IQR, 2.9) years]. Muscle volume (MV) and muscle belly length for m. rectus femoris, semitendinosus, gastrocnemius medialis, and tibialis anterior were defined from three-dimensional freehand ultrasound acquisitions. A fixed dynamometer was used to assess maximal voluntary isometric contractions for knee extension, knee flexion, plantar flexion, and dorsiflexion from which maximal joint torque (MJT) was calculated. Selective motor control (SMC) was assessed on a 5-point scale for the children with SCP. First, the anthropometrics, strength, and muscle size parameters were compared between the cohorts. Significant differences for all muscle size and strength parameters were found (p ≤ 0.003), except for joint torque per MV for the plantar flexors. Secondly, the associations of anthropometrics, muscle size, gross motor function classification system (GMFCS) level, and SMC with MJT were investigated using univariate and stepwise multiple linear regressions. The associations of MJT with growth-related parameters like age, weight, and height appeared strongest in the TD cohort, whereas for the SCP cohort, these associations were accompanied by associations with SMC and GMFCS. The stepwise regression models resulted in ranges of explained variance in MJT from 29.3 to 66.3% in the TD cohort and from 16.8 to 60.1% in the SCP cohort. Finally, the MJT deficit observed in the SCP cohort was further investigated using the TD regression equations to estimate norm MJT based on height and potential MJT based on MV. From the total MJT deficit, 22.6-57.3% could be explained by deficits in MV. This investigation confirmed the disproportional decrease in muscle size and muscle strength around the knee and ankle joint in children with SCP, but also highlighted the large variability in the contribution of muscle size to muscle weakness.

Project description:Background: Walking problems in children with cerebral palsy (CP) can in part be explained by limited selective motor control. Muscle synergy analysis is increasingly used to quantify altered neuromuscular control during walking. The early brain injury in children with CP may lead to a different development of muscle synergies compared to typically developing (TD) children, which might characterize the abnormal walking patterns. Objective: The overarching aim of this review is to give an overview of the existing studies investigating muscle synergies during walking in children with CP compared to TD children. The main focus is on how muscle synergies differ between children with CP and TD children, and we examine the potential of muscle synergies as a measure to quantify and predict treatment outcomes. Methods: Bibliographic databases were searched by two independent reviewers up to 22 April 2019. Studies were included if the focus was on muscle synergies of the lower limbs during walking, obtained by a matrix factorization algorithm, in children with CP. Results: The majority (n = 12) of the 16 included studies found that children with CP recruited fewer muscle synergies during walking compared to TD children, and several studies (n = 8) showed that either the spatial or temporal structure of the muscle synergies differed between children with CP and TD children. Variability within and between subjects was larger in children with CP than in TD children, especially in more involved children. Muscle synergy characteristics before treatments to improve walking function could predict treatment outcomes (n = 3). Only minimal changes in synergies were found after treatment. Conclusions: The findings in this systematic review support the idea that children with CP use a simpler motor control strategy compared to TD children. The use of muscle synergy analysis as a clinical tool to quantify altered neuromuscular control and predict clinical outcomes seems promising. Further investigation on this topic is necessary, and the use of muscle synergies as a target for development of novel therapies in children with CP could be explored.

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A Coupled Mechanobiological Model of Muscle Regeneration In Cerebral Palsy

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