The meal distribution of proteins throughout the day is usually skewed. However, its physiological implications and the effects of better protein distribution on muscle volume are largely unknown. Here, using the two-meals-per-day feeding model, we find that protein intake at the early active phase promotes overloading-induced muscle hypertrophy, in a manner dependent on the local muscle clock. Mice fed branched-chain amino acid (BCAA)-supplemented diets at the early active phase demonstrate skeletal muscle hypertrophy. However, distribution-dependent effects are not observed in ClockΔ19 or muscle-specific Bmal1 knockout mice. Additionally, we examined the relationship between the distribution of proteins in meals and muscle functions, such as skeletal muscle index and grip strength in humans. Higher muscle functions were observed in subjects who ingested dietary proteins mainly at breakfast than at dinner. These data suggest that protein intake at breakfast may be better for the maintenance of skeletal muscle mass.

Chronic Kidney Disease (CKD) is increasing in incidence and has become a worldwide health problem. Sleep disorders are prevalent in patients with CKD raising the possibility that these patients have a disorganized circadian timing system. Here, we examined the effect of adenine-induced tubulointerstitial nephropathy on the circadian system in mice. Compared to controls, adenine-treated mice showed serum biochemistry evidence of CKD as well as increased kidney expression of inflammation and fibrosis markers. Mice with CKD exhibited fragmented sleep behavior and locomotor activity, with lower degrees of cage activity compared to mice without CKD. On a molecular level, mice with CKD exhibited low amplitude rhythms in their central circadian clock as measured by bioluminescence in slices of the suprachiasmatic nucleus of PERIOD 2::LUCIFERASE mice. Whole animal imaging indicated that adenine treated mice also exhibited dampened oscillations in intact kidney, liver, and submandibular gland. Consistently, dampened circadian oscillations were observed in several circadian clock genes and clock-controlled genes in the kidney of the mice with CKD. Finally, mice with a genetically disrupted circadian clock (Clock mutants) were treated with adenine and compared to wild type control mice. The treatment evoked worse kidney damage as indicated by higher deposition of gelatinases (matrix metalloproteinase-2 and 9) and adenine metabolites in the kidney. Adenine also caused non-dipping hypertension and lower heart rate. Thus, our data indicate that central and peripheral circadian clocks are disrupted in the adenine-treated mice, and suggest that the disruption of the circadian clock accelerates CKD progression.

In addition to the development of chrononutrition, food ingredients have been demonstrated to contribute to expression changes in the peripheral clock genes responsible for circadian rhythms. Passion fruit seeds extract (PFSE) contains a high concentration of piceatannol that exhibits many physiological activities; however, whether PFSE and piceatannol affect clock genes is not known with certainty. In this study, we evaluated the effects of PFSE and piceatannol on the rhythm of PER2 using bioluminescence in mPer2(Luc) knock-in mice and their embryonic fibroblasts. Piceatannol was demonstrated to advance and delay the phase of PER2::LUC oscillation owing to differences in timing of treatment in vitro. In the in vivo imaging system, oral administration of piceatannol significantly advanced the luminescence rhythm of PER2::LUC in peripheral organs. Furthermore, piceatannol recovered the phase change of PER2::LUC disturbed by high-fat diet intake. These findings indicate that piceatannol affects peripheral clock gene expression and may prevent circadian disturbance.

Dietary protein intake is important for skeletal muscle protein synthesis. In this study, we investigated the differential effect of protein sources on hypertrophy of plantaris muscle induced by surgical ablation of gastrocnemius and soleus muscles. Six-week old mice were fed diets containing caseinate, whey, or soy as protein sources for 2 weeks. Plantaris muscle hypertrophy was induced by a unilateral ablation of synergistic muscles after a week. Food intake of soy protein-fed mice was higher than that of caseinate and whey-fed mice, resulting in higher body and fat weights. Plantaris muscle weight in sham-operated mice was not different across the groups. Overload-operated plantaris muscle weight and increased ratio of overloaded muscle to sham-operated muscle weights were higher in caseinate-fed mice than in whey- and soy protein-fed mice, suggesting caseinate as a promising protein source for muscle hypertrophy.

Muscle mass is controlled by the balance between muscle synthesis and degradation. Although nutrition is important for the maintenance of muscle mass and growth, the effects of feeding time have remained unclear. In the present study, we aimed to evaluate the effects of day- or night-time-restricted feeding on the muscle volume using muscle atrophy and hypertrophy mouse models. The day- and night-time-restricted feeding was conducted from zeitgeber time 2 (ZT2) to ZT10 and ZT14 to ZT22, respectively. In the unilateral immobilization-induced atrophy model, the decrease in immobilized muscle weight did not significantly change with the feeding time. However, the contralateral non-immobilized muscle weight was lower in the mice fed at day time (inactive phase) than in those fed at night time (active phase). In the overloading-induced hypertrophy model, muscle hypertrophy and protein synthesis were attenuated by day-time feeding. These results suggest that day-time feeding attenuated muscle growth via the inhibition of muscle synthesis. Feeding at an irregular time such as a late-night meal could be detrimental for muscle growth.

Background: Atrogin1, which is one of the key genes for the promotion of muscle atrophy, exhibits day-night variation. However, its mechanism and the role of its day-night variation are largely unknown in a muscle atrophic context. Methods: The mice were induced a muscle atrophy by hindlimb-unloading (HU). To examine a role of circadian clock, Wild-type (WT) and Clock mutant mice were used. To test the effects of a neuronal effects, an unilateral ablation of sciatic nerve was performed in HU mice. To test a timing-dependent effects of weight-bearing, mice were released from HU for 4 h in a day at early or late active phase (W-EAP and W-LAP groups, respectively). Findings: We found that the day-night oscillation of Atrogin1 expression was not observed in Clock mutant mice or in the sciatic denervated muscle. In addition, the therapeutic effects of weight-bearing were dependent on its timing with a better effect in the early active phase. Interpretation: These findings suggest that the circadian clock controls the day-night oscillation of Atrogin1 expression and the therapeutic effects of weight-bearing are dependent on its timing. (C) 2018 The Authors. Published by Elsevier B.V.