Background

Skeletal muscle mitochondrial function is reduced in individuals with insulin resistance and has been suggested to be an important determinant of metabolic health. In healthy lean participants, mitochondrial oxidative capacity follows a day-night rhythm with peak capacity in the evening. Whether mitochondrial function also displays day-night rhythmicity in insulin resistant participants is unknown.

Methods

Twelve male obese volunteers with impaired glucose tolerance and insulin sensitivity stayed in a metabolic research unit for 2 days under free living conditions with regular meals. Indirect calorimetry was performed at five time points (8 AM, 1 PM, 6 PM, 11 PM, 4 AM), followed by a muscle biopsy. Mitochondrial oxidative capacity was measured in permeabilized muscle fibers using high-resolution respirometry. Skeletal muscle gene expression was measured using qPCR.

Results

Skeletal muscle mitochondrial function, as defined by state 3 and uncoupled respiration did not display rhythmicity (p > 0.05). The expression of circadian core clock genes BMAL1 and REV-ERBa showed a clear day-night rhythm (p < 0.001), peaking at the end of the waking period. Remarkably, the repressor clock gene PER2 did not show rhythmicity (p > 0.05), whereas PER1 and PER3 were strongly rhythmic (p < 0.001), with a trough in the evening. On the whole-body level resting energy expenditure was highest in the late evening (p < 0.001). Respiratory exchange ratio did not decrease in the night, indicating metabolic inflexibility.

Conclusions

Mitochondrial oxidative capacity does not show a day-night rhythm in obese participants with impaired glucose tolerance and insulin sensitivity. The lack of rhythmicity in mitochondrial function was paralleled by metabolic inflexibility over 24 hours. In addition, gene expression of PER2 in skeletal muscle indicates that rhythmicity of the negative feedback loop of the molecular clock is disturbed.