Day-night rhythm of skeletal muscle metabolism is disturbed in older, metabolically compromised individuals

Abstract

Objective Skeletal muscle mitochondrial function and energy metabolism displays day-night rhythmicity in healthy, young individuals. Twenty-four-hour 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 remains 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 5 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. Results Mitochondrial oxidative capacity did not display rhythmicity. The expression of circadian core clock genes BMAL1 and REV-ERBα 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 during 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. ClinicalTrials.gov ID NCT03733743 .

The influence of bright and dim light on substrate metabolism, energy expenditure and thermoregulation in insulin-resistant individuals depends on time of day

“…Melatonin started to rise 2-4 h before habitual bedtime upon Bright day-Dim evening, which is in line with the reported range of DLMO in young healthy volunteers [22][23][24]. In contrast, CBT data (n = 8) consistently indicated a relatively early occurrence of the CBT nadir (range of the mean of all nights between 00:00 and 01:15 h) in line with another study in insulin-resistant men of similar age [25], which seems to be phaseadvanced compared with younger participants (i.e. between 04:00 and 06:00 h [26,27]).…”

Three weeks of time-restricted eating improves glucose homeostasis in adults with type 2 diabetes but does not improve insulin sensitivity: a randomised crossover trial

“…Despite the fact that TRE is sometimes accompanied by (unintended) weight loss [4-6, 9, 10, 12, 13], which inherently improves metabolic health, it has also been reported to improve metabolic health in the absence of weight loss [8], indicating that additional mechanisms underlie the effects of TRE. In this context, individuals with impaired metabolic health display aberrations in rhythmicity of metabolic processes such as glucose homeostasis [14,15], mitochondrial oxidative capacity [16] and wholebody substrate oxidation [16] compared with the rhythms found in healthy, lean individuals [14,15,17]. Disruption of circadian rhythmicity is proposed to contribute to the impaired matching of substrate utilisation with substrate availability, which is associated with type 2 diabetes [18].…”

Regulation of diurnal energy balance by mitokines

“…Whole muscle lipid composition also showed variations across the day-night cycle [33]. The same group showed recently that in older, overweight, and metabolically compromised individuals the diurnal rhythmicity in skeletal muscle mitochondrial oxidative capacity and molecular clock gene expression was disturbed [34], again linking metabolic disorders with impaired diurnal rhythmicity. Of note, physical exercise, which is one of the most potent ways for improvement of muscle insulin sensitivity, is also a strong external zeitgeber for entrainment of the peripheral muscle clock.…”