Mitochondrial Function, But Not Glucose Uptake, Is Disrupted In Skeletal Muscle from Bmal1-/- Mice

Molecular clocks regulate circadian rhythms including muscle function and metabolism. Mice lacking Bmal1, a circadian clock transcription factor, showed a decreased in mitochondrial density in skeletal muscle. We hypothesize that mitochondrial function and glucose uptake are compromised in skeletal muscle of Bmal1^-/- mice. O₂ consumption was measured by polarography in mitochondria from 18 week-old gastrocnemius muscles. Content of respiratory complexes, UCP3 and VDAC1 was measured in isolated mitochondria by western blot. Glucose uptake was measured with [³H] glucose upon insulin stimulation in the soleus muscles of 13 and 36 week-old mice. Blood glucose was measured using a commercial glucose meter in 7, 13 and 36 week-old mice. Serum insulin was measured with an Elisa kit in 13 and 36 week-old mice. Respiration states 3 (ADP-driven) and 5 (uncoupled) were 47±6% and 50±8% lower in mitochondria isolated from the gastrocnemius muscles of Bmal1^-/- vs. control mice. There were no differences in the content of respiratory complexes, UCP3 and VDAC1. Blood glucose was 61% higher in 7 week-old Bmal1^-/- mice but there was no difference at other ages. Serum insulin wassignificantly lower in 36 week-old Bmal1^-/- mice. Basal and insulin-stimulated glucose uptake rates were not different in soleus muscles at any age. We suggest that the molecular clock regulates mitochondrial function but not glucose uptake in mice. Research supported by RC1ES018636-02 to KAE and FHA and R01AR045617 to KAE.