Objective: A disturbed day-night rhythm is associated with metabolic perturbations that can lead to obesity and type 2 diabetes mellitus (T2DM). In skeletal muscle, a reduced oxidative capacity is also associated with the development of T2DM. However, whether oxidative capacity in skeletal muscle displays a day-night rhythm in humans has so far not been investigated.
Methods: Lean, healthy subjects were enrolled in a standardized living protocol with regular meals, physical activity and sleep to reflect our everyday lifestyle. Mitochondrial oxidative capacity was examined in skeletal muscle biopsies taken at five time points within a 24-hour period.
Results: Core-body temperature was lower during the early night, confirming a normal day-night rhythm. Skeletal muscle oxidative capacity demonstrated a robust day-night rhythm, with a significant time effect in ADP-stimulated respiration (state 3 MO, state 3 MOG and state 3 MOGS, p < 0.05). Respiration was lowest at 1 PM and highest at 11 PM (state 3 MOGS: 80.6 ± 4.0 vs. 95.8 ± 4.7 pmol/mg/s). Interestingly, the fluctuation in mitochondrial function was also observed in whole-body energy expenditure, with peak energy expenditure at 11 PM and lowest energy expenditure at 4 AM (p < 0.001). In addition, we demonstrate rhythmicity in mRNA expression of molecular clock genes in human skeletal muscle.
Conclusions: Our results suggest that the biological clock drives robust rhythms in human skeletal muscle oxidative metabolism. It is tempting to speculate that disruption of these rhythms contribute to the deterioration of metabolic health associated with circadian misalignment.
Keywords: BMAL1, brain and muscle ARNT-like 1; BMI, body mass index; Biological rhythm; CLOCK, circadian locomotor output cycles kaput; CRY, cryptochrome; Energy metabolism; FCCP, carbonyl cyanide-4-trifluoromethoxyphenylhydrazone; Mitochondria; Molecular clock; NADH, reduced nicotinamide adenine dinucleotide; Oxidative capacity; PER, period; RER, respiratory exchange ratio; RT-QPCR, Real-Time Quantitative Polymerase Chain Reaction; Skeletal muscle; T2DM, type 2 diabetes mellitus; TCA cycle, tricarboxylic acid cycle.