MicroRNA-494 regulates mitochondrial biogenesis in skeletal muscle through mitochondrial transcription factor A and Forkhead box j3.

MicroRNAs (miRNAs) are important posttranscriptional regulators of various biological pathways. In this study, we focused on the role of miRNAs during mitochondrial biogenesis in skeletal muscle. The expression of miR-494 was markedly decreased in murine myoblast C₂C₁₂ cells during myogenic differentiation, accompanied by an increase in mtDNA. Furthermore, the expression of predicted target genes for miR-494, including mitochondrial transcription factor A (mtTFA) and Forkhead box j3 (Foxj3), was posttranscriptionally increased during myogenic differentiation. Knockdown of miR-494 resulted in increased mitochondrial content and upregulation of mtTFA and Foxj3 at the protein level. A 3'-untranslated region reporter assay revealed that miR-494 knockdown directly upregulated the luciferase activity of mtTFA and Foxj3. All of these observations were reversed by overexpression of miR-494. Furthermore, the miR-494 content significantly decreased after endurance exercise in C57BL/6J mice, accompanied by an increase in expression of mtTFA and Foxj3 proteins. These results suggest that miR-494 regulates mitochondrial biogenesis by downregulating mtTFA and Foxj3 during myocyte differentiation and skeletal muscle adaptation to physical exercise.

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