Effect of Denervation on the Regulation of Mitochondrial Transcription Factor a Expression in Skeletal Muscle

The most rapid decline in myofiber size and mitochondrial content during denervation, a muscle disuse model, occurs during the first week following the onset of the stimulus. In this study, we analyzed the expression of Tfam, a critical mitochondrial transcription factor involved in the orchestration of mitochondrial biogenesis, at multiple levels during denervation. Tfam transcriptional activation was depressed during the early stages of denervation but was counteracted by increases in the stability of the Tfam mRNA, an effect which could not be accounted for by the protein expression of select RNA-binding proteins. Denervation reduced Tfam mitochondrial import, which was associated with reductions in mitochondrial DNA transcription. These data highlight that there are multiple factors affecting the expression and activity of the Tfam transcript and protein during denervation. This work also emphasizes the importance of mitochondrial protein import in the regulation of Tfam function, and subsequently mitochondrial content, during muscle disuse.