Retrospective transcriptomic analysis indicates temporal dysregulation of mitochondrial genes and metabolic pathways after volumetric muscle loss injury

Volumetric muscle loss (VML) injury results in the irrecoverable loss of muscle mass and strength and alters the metabolic capacity of the remaining muscle tissue. The primary objective of this retrospective study was to leverage existing RNA-seq datasets to investigate mitochondria and metabolic transcriptome changes after VML injury. The datasets were extracted from publicly available sources and included a bulk RNA-seq dataset (Rattus norvegicus) and a single-cell RNA-seq dataset (Mus musculus) that combined provided a transcriptional landscape out to 42 days post-injury (dpi). The Broad Institute's MitoCarta3.0 database was used to identify mitochondrial-associated genes and pathways for the analysis. There was a robust downregulation of genes in the bulk RNA-seq dataset out to 28 dpi. Gene set enrichment analysis revealed that these genes contributed to oxidative phosphorylation, fatty-acid oxidation, and carbohydrate metabolism. A changing metabolic transcriptional landscape was evident in the single-cell RNA-seq dataset as several cell types (e.g., satellite cells, macrophages, and fibro-adipogenic cells) had upregulated gene sets (e.g., oxidative phosphorylation) that switched to downregulated after 14 dpi. Results from this study complement physiological studies that report dysfunctional mitochondrial bioenergetics, particularly for carbohydrate and free-fatty acid carbon sources, both immediately and chronically after VML injury. These findings also provide targets for monitoring the success of future interventions or directly manipulating in attempts to improve whole-muscle metabolic function.