Muscle Elongation Transcriptome
While contractures involve impaired longitudinal muscle growth, the precise pathophysiology of this deficit in muscle elongation is unclear. Specifically, the biological mechanisms and genes regulating muscle length are unknown.
Using our mouse model of NBPI, the Cornwall Lab recently observed elevated levels of DNA methylation in denervated muscles, and that pharmacologic inhibition of DNA methylation prevents contractures. These findings suggest a role of gene dysregulation in disrupting muscle elongation and modulating contractures.
Thus, to develop novel contracture therapies, we must first identify specific genes central to muscle elongation. With our current work, we seek to:
- elucidate the molecular/transcriptomic profile of elongating muscles, or "elongation transcriptome", and
- identify and validate individual genes in that transcriptome with roles in muscle cell elongation
Through RNA-sequencing and gene ontology analyses, we have preliminary identified a list of several differentially expressed genes that are upregulated in elongating muscles. Uniquely, these genes are largely related to ECM composition, binding, and signaling, further underscoring the importance of exploring the interface between a growing muscle and its extracellular matrix.
In addition, this list includes genes implicated in clinical disorders such as muscular dystrophy and distal arthrogryposis, although the roles of these genes in muscle length in these disorders have not been previously identified.
We are currently in the process of validating the role of these genes in muscle elongation through a mix of loss and gain of function approaches on both mouse and cell culture models. While ongoing, we have presented our preliminary findings at the ORS 2026 Annual Meeting1
Uncovering novel genes that specifically modulates muscle length will advance our understanding of this overlooked dimension of muscle growth. Furthermore, this list may provide novel targets for treating other clinical disorders characterized by abnormally short muscles, or "myobrevopathies."
This research has been funded by the National Institutes of Health - Eunice Kennedy Shriver National Institute of Child Health and Human Development.
1, Identification of Genes Central to Skeletal Muscle Elongation. Symson L and Collodetti de Souza B, Velaga, G, Shay-Winkler K, Goh Q, Cornwall R. ORS 2026 Annual Meeting, Charlotte, NC.
