NOS isoform-specific regulation of basal but not exercise-induced mitochondrial biogenesis in mouse skeletal muscle

Nitric oxide is a potential regulator of mitochondrial biogenesis. Therefore, we investigated if mice deficient in endothelial nitric oxide synthase (eNOS −/− ) or neuronal NOS (nNOS −/− ) have attenuated activation of skeletal muscle mitochondrial biogenesis in response to exercise. eNOS −/− , nNOS −/− and C57Bl/6 (CON) mice (16.3 ± 0.2 weeks old) either remained in their cages (basal) or ran on a treadmill (16 m min −1 , 5% grade) for 60 min ( n = 8 per group) and were killed 6 h after exercise. Other eNOS −/− , nNOS −/− and CON mice exercise trained for 9 days (60 min per day) and were killed 24 h after the last bout of exercise training. eNOS −/− mice had significantly higher nNOS protein and nNOS −/− mice had significantly higher eNOS protein in the EDL, but not the soleus. The basal mitochondrial biogenesis markers NRF1, NRF2α and mtTFA mRNA were significantly ( P < 0.05) higher in the soleus and EDL of nNOS −/− mice whilst basal citrate synthase activity was higher in the soleus and basal PGC-1α mRNA higher in the EDL. Also, eNOS −/− mice had significantly higher basal citrate synthase activity in the soleus but not the EDL. Acute exercise increased ( P < 0.05) PGC-1α mRNA in soleus and EDL and NRF2α mRNA in the EDL to a similar extent in all genotypes. In addition, short-term exercise training significantly increased cytochrome c protein in all genotypes ( P < 0.05) in the EDL. In conclusion, eNOS and nNOS are differentially involved in the basal regulation of mitochondrial biogenesis in skeletal muscle but are not critical for exercise-induced increases in mitochondrial biogenesis in skeletal muscle.