Temporal Dynamics of Gene and Protein Signatures Following Volumetric Muscle Loss

Ishita Jain¹Beu Oropeza¹Caroline Hu²Gladys Chiang²Sree Aravindan²Renato Reyes²Daniel Yuhang Li¹Paul Cheng¹Ngan F Huang^1*

• ¹Stanford University, Stanford, United States
• ²Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States

Volumetric muscle loss (VML) is characterized by permanent tissue impairment resulting from critically-sized muscle loss. We performed time-series transcriptomic and proteomic analyses to reveal key mediators of irreversible pathological remodeling after induction of VML in mice. The dynamics of gene and protein expression patterns were analyzed for up to three weeks after muscle injury. RNA Sequencing revealed transcriptional patterns that show rapid upregulation or downregulation shortly after injury, among which a subset of genes failed to return to pre-injury levels within 3 weeks after VML. Time-series analysis revealed gene clusters with sustained upregulation after 3 weeks, including those associated with extracellular matrix remodeling and inflammation, whereas the gene clusters having sustained downregulation were associated with mitochondrial function and metabolism. We further identified SPI1 and SP1 as novel molecular mediators of the pathological remodeling process. This work demonstrates the utility of time-series analysis to reveal dysregulated pathways in the setting of VML.