| First Author | Queiroz AL | Year | 2021 |
| Journal | Mol Metab | Volume | 51 |
| Pages | 101226 | PubMed ID | 33812060 |
| Mgi Jnum | J:317099 | Mgi Id | MGI:6714623 |
| Doi | 10.1016/j.molmet.2021.101226 | Citation | Queiroz AL, et al. (2021) The MicroRNA miR-696 is regulated by SNARK and reduces mitochondrial activity in mouse skeletal muscle through Pgc1alpha inhibition. Mol Metab 51:101226 |
| abstractText | OBJECTIVE: MicroRNAs (miRNA) are known to regulate the expression of genes involved in several physiological processes including metabolism, mitochondrial biogenesis, proliferation, differentiation, and cell death. METHODS: Using "in silico" analyses, we identified 219 unique miRNAs that potentially bind to the 3'UTR region of a critical mitochondrial regulator, the peroxisome proliferator-activated receptor gamma coactivator (PGC) 1 alpha (Pgc1alpha). Of the 219 candidate miRNAs, miR-696 had one of the highest interactions at the 3'UTR of Pgc1alpha, suggesting that miR-696 may be involved in the regulation of Pgc1alpha. RESULTS: Consistent with this hypothesis, we found that miR-696 was highly expressed in the skeletal muscle of STZ-induced diabetic mice and chronic high-fat-fed mice. C2C12 muscle cells exposed to palmitic acid also exhibited a higher expression of miR-696. This increased expression corresponded with a reduced expression of oxidative metabolism genes and reduced mitochondrial respiration. Importantly, reducing miR-696 reversed decreases in mitochondrial activity in response to palmitic acid. Using C2C12 cells treated with the AMP-activated protein kinase (AMPK) activator AICAR and skeletal muscle from AMPKalpha2 dominant-negative (DN) mice, we found that the signaling mechanism regulating miR-696 did not involve AMPK. In contrast, overexpression of SNF1-AMPK-related kinase (SNARK) in C2C12 cells increased miR-696 transcription while knockdown of SNARK significantly decreased miR-696. Moreover, muscle-specific transgenic mice overexpressing SNARK exhibited a lower expression of Pgc1alpha, elevated levels of miR-696, and reduced amounts of spontaneous activity. CONCLUSIONS: Our findings demonstrate that metabolic stress increases miR-696 expression in skeletal muscle cells, which in turn inhibits Pgc1alpha, reducing mitochondrial function. SNARK plays a role in this process as a metabolic stress signaling molecule inducing the expression of miR-696. |
