Time‐restricted feeding during the inactive phase abolishes the daily rhythm in mitochondrial respiration in rat skeletal muscle

Abstract

Shift‐workers show an increased incidence of type 2 diabetes mellitus (T2DM). A possible mechanism is the disruption of the circadian timing of glucose homeostasis. Skeletal muscle mitochondrial function is modulated by the molecular clock. We used time‐restricted feeding (TRF) during the inactive phase to investigate how mistimed feeding affects muscle mitochondrial metabolism. Rats on an ad libitum (AL) diet were compared to those that could eat only during the light (inactive) or dark (active) phase. Mitochondrial respiration, metabolic gene expressions, and metabolite concentrations were determined in the soleus muscle. Rats on AL feeding or dark‐fed TRF showed a clear daily rhythm in muscle mitochondrial respiration. This rhythm in mitochondrial oxidative phosphorylation capacity was abolished in light‐fed TRF animals and overall 24h respiration was lower. The expression of several genes involved in mitochondrial biogenesis and the fission/fusion machinery was altered in light‐fed animals. Metabolomics analysis indicated that light‐fed animals had lost rhythmic levels of α‐ketoglutarate and citric acid. Contrastingly, lipidomics showed that light‐fed animals abundantly gained rhythmicity in levels of triglycerides. Furthermore, while the RER shifted entirely with the food intake in the light‐fed animals, many measured metabolic parameters (e.g., activity and mitochondrial respiration) did not strictly align with the shifted timing of food intake, resulting in a mismatch between expected metabolic supply/demand (as dictated by the circadian timing system and light/dark‐cycle) and the actual metabolic supply/demand (as dictated by the timing of food intake). These data suggest that shift‐work impairs mitochondrial metabolism and causes metabolic inflexibility, which can predispose to T2DM.

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

“…Rats fed a normal diet limited to ten hours in the daytime inactive period showed disrupted circadian rhythms in the rate of mitochondrial respiration in skeletal muscle. This mimics the metabolic dysfunction observed in human subjects with type-2 diabetes and in night-shift workers, who have a greatly increased risk of type-2 diabetes [ 61 ]. Therefore, fasting during the active period of the circadian cycle may result in an increased risk of metabolic disease if exercise is not performed or if calories are not restricted during the inactive feeding period.…”

“…Under fasting conditions when glutamate dehydrogenase activity is high, αkg levels rise [ 60 ]. This regulation might be partly responsible for the diurnal fluctuations in skeletal muscle αkg levels [ 61 ]. Supplementing with αkg has been shown to increase the lifespan of C. elegans [ 62 ], Drosophila [ 63 ], and mice [ 64 ], while plasma αkg levels decline substantially with aging in mammals [ 65 ].…”

Fasting: From Physiology to Pathology

“…[ 41,178 ] In addition, there is no denying that all three regimens can affect gut microbiome, autophagy, and mitochondrial function. [ 37,70,122,153,186,249,300,334 ]…”

“…[57,68,69] In line with these effects, TRF plays an important role in maintaining the daily rhythm in muscle mitochondrial respiration, and can reset obesity-induced disruption of the muscle clock and restore muscle function. [66,70] TRF can restore the dysregulated WAT clock caused by constant light exposure, albeit the underlying mechanisms remain unclear. [58] Nevertheless, it has been shown that TRF could affect the circadian rhythms of several regulators crucial for adipose function, including fibroblast growth factor 21 (FGF21), [71] and hormonesensitive lipase (HSL).…”

Chrononutrition—When We Eat Is of the Essence in Tackling Obesity

“…The process of mitochondrial biogenesis is generally associated with improved cell health and has been reported in various cell types [ 324 , 325 , 326 ]. Inactive phase feeding in rats leads to an altered regulation of mitochondrial biogenesis [ 327 ]. Dietary interventions such as whole-grain bioactive compounds and various polyphenolic compounds also contribute to mitochondrial biogenesis, mainly via the SIRT- PGC1α pathway [ 328 , 329 , 330 ].…”