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Published on: October 15, 2019
NOS isoform-specific regulation of basal but not exercise-induced mitochondrial biogenesis in mouse skeletal muscle
G D Wadley1, J Choate, G K McConell
1Department of Physiology, University of Melbourne, Parkville, Victoria, 3010, Australia. gdwadley@unimelb.edu.au
Abstract:
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, NRF2alpha 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-1alpha 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-1alpha mRNA in soleus and EDL and NRF2alpha 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.
Insights
Mice lacking endothelial nitric oxide synthase (eNOS) or neuronal nitric oxide synthase (nNOS) show altered basal mitochondrial biogenesis. However, exercise-induced mitochondrial adaptations in skeletal muscle occur regardless of eNOS or nNOS.
Area of Science:
- Exercise Physiology
- Mitochondrial Biology
- Nitric Oxide Signaling
Background:
- Nitric oxide (NO) is implicated in regulating mitochondrial biogenesis.
- Endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) produce NO.
- The role of eNOS and nNOS in exercise-induced mitochondrial adaptations in skeletal muscle remains unclear.
Purpose of the Study:
- To investigate the role of eNOS and nNOS in basal and exercise-induced mitochondrial biogenesis in mouse skeletal muscle.
- To determine if mice deficient in eNOS or nNOS exhibit attenuated skeletal muscle mitochondrial biogenesis responses to exercise.
Main Methods:
- Utilized eNOS knockout (eNOS-/-), nNOS knockout (nNOS-/-), and wild-type (CON) mice.
- Assessed basal and exercise-induced changes in mitochondrial biogenesis markers (mRNA and protein) in skeletal muscles (soleus and EDL).
- Mice underwent acute exercise or short-term exercise training protocols.
Main Results:
- nNOS-/- mice exhibited higher basal mitochondrial biogenesis markers (NRF1, NRF2α, mtTFA mRNA, PGC-1α mRNA, citrate synthase activity) in skeletal muscle.
- eNOS-/- mice showed higher basal citrate synthase activity in the soleus.
- Acute exercise and short-term training increased mitochondrial markers similarly across all genotypes, indicating no critical role for eNOS or nNOS in exercise adaptations.
Conclusions:
- eNOS and nNOS play differential roles in the basal regulation of skeletal muscle mitochondrial biogenesis.
- Neither eNOS nor nNOS is essential for the exercise-induced increases in mitochondrial biogenesis in skeletal muscle.
