Day-Night Rhythm of Skeletal Muscle Metabolism is Disturbed in Older, Metabolically Compromised Individuals

Jakob Wefers, Niels J. Connell, Ciarán E. Fealy, Charlotte Andriessen, ... Patrick Schrauwen

Objective

Skeletal muscle mitochondrial function and energy metabolism displays day-night rhythmicity in healthy, young individuals. 24-h rhythmicity of metabolism has been implicated in the etiology of age-related metabolic disorders. Whether day-night rhythmicity in skeletal muscle mitochondrial function and energy metabolism is altered in older, metabolically comprised humans is so far unknown.

Methods

Twelve male overweight 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 (8AM, 1PM, 6PM, 11PM, 4AM), followed by a muscle biopsy. Mitochondrial oxidative capacity was measured in permeabilized muscle fibers using high-resolution respirometry.

Results

Mitochondrial oxidative capacity did not display rhythmicity. 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, whereas PER1 and PER3 were strongly rhythmic (p < 0.001). 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 older, overweight participants with impaired glucose tolerance and insulin sensitivity. In addition, gene expression of PER2 in skeletal muscle indicates that rhythmicity of the negative feedback loop of the molecular clock is disturbed.