GSE185530
Long non-coding RNA Tug1 modulates mitochondrial and myogenic responses to exercise in skeletal muscle
Mitochondrial adaptations play a central role in the beneficial effects of exercise, particularly in metabolically active tissues such as skeletal muscle. Despite this, the molecular regulators of mitochondrial adaptive responses have not yet been fully elucidated. The long non-coding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) interacts with the master transcriptional regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a). In skeletal muscle of young healthy humans (n=14), we observed that TUG1 gene expression was elevated following an acute bout of continuous, moderate intensity cycling exercise and this positively correlated with PPARGC1A gene expression. Therefore, we hypothesised that TUG1 may modulate skeletal muscle mitochondrial responses to exercise. Knockdown (KD) of Tug1 in differentiating mouse myotubes resulted in altered mitochondrial morphology and impaired mitochondrial respiratory function, which was accompanied by greater myosin heavy chain slow isoform protein expression, despite lower Ppargc1a gene and MFN2 protein expression. Tug1 KD prevented the induction of Ppargc1a expression from a Ca2+ mediated stimulus (caffeine) yet the response to an AMPK agonist (AICAR ) was unaffected. RNA-sequencing revealed that Tug1 KD affected genes relating to mitochondrial Ca2+ transport and downstream targets of PGC-1a. Finally, in response to electrical pulse stimulation (EPS), an in vitro model of exercise in myotubes, there were ~300 genes whose upregulation in response to EPS was either blunted or augmented by Tug1 KD, including regulators of muscle differentiation and myogenesis. These data demonstrate that the lncRNA Tug1 is a novel regulator of skeletal muscle transcriptional responses to exercise and myogenesis. Overall design: RNA profiles of myotubes (mouse C2C12) with or without Tug1 knockdown under three conditions: unstimulated (rest), immediately after and 3 hours after 3 hours of electrical pulse stimulation.