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Differential DNA Methylation and Transcriptional Signatures Characterize Impairment of Progenitor Cells in Pediatric Human Muscle Contractures Following Brain Injury [array]

ABSTRACT: Limb contractures are a debilitating and progressive consequence of a wide range of pediatric conditions that affect skeletal muscles, including perinatal brain injury causing cerebral palsy (CP). While several rehabilitation therapies are currently used in the clinical setting, their long-term effectiveness in treating contractures is marginal since they do not change underlying muscle biological properties. Therefore, new therapies based on a biological understanding of contracture development are needed. Here we show that myoblast progenitor cells from contractured muscle in children with CP had higher rates of proliferation than control cells from typically developing children. This phenotype was associated with upregulation of DNMT3a and patterns of DNA hypermethylation and gene expression that favored cell expansion over quiescence. Treatment of CP progenitors with 5-azacytidine (AZA), a DNMT inhibitor and hypomethylating agent, normalized this epigenetic imprint and promoted exit from mitosis. Together with previous studies demonstrating reduction in myoblast differentiation capacity, these data suggest that mechanisms of early myofiber growth and establishment of an adult population of quiescent stem cells could be compromised in CP. Hypomethylating agents like AZA could be used to rescue myogenesis and promote muscle growth in contractured muscle and thus may represent a new approach to treating this devastating condition

ORGANISM(S): Homo sapiens

PROVIDER: GSE171318 | GEO | 2021/04/02

REPOSITORIES: GEO

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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.

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Differential DNA Methylation and Transcriptional Signatures Characterize Impairment of Progenitor Cells in Pediatric Human Muscle Contractures Following Brain Injury [array]

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