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

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 We performed DNA methylation analysis of cultured proliferating satellite cell-derived myoblast precursors from contractured cerebral palsy (CP) muscles and typically developing control (N) muscles, treated and non-treated with hypomethylating agent 5-azacytidine (AZA)