Day-Night Oscillation of Atrogin1 and Timing-Dependent Preventive Effect of Weight-Bearing on Muscle Atrophy

Abstract

BackgroundAtrogin1, 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.MethodsThe 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).FindingsWe 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.InterpretationThese 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.FundCouncil for Science, Technology, and Innovation, SIP, “Technologies for creating next-generation agriculture, forestry, and fisheries”.

Integrated RNA-seq Analysis Indicates Asynchrony in Clock Genes between Tissues under Spaceflight

“…Since TFs of these genes form core clock components in circadian rhythm mechanisms [ 31 ], these clock genes could play a role as key regulators associated with underlying mechanisms of physiology and metabolism under spaceflight [ 18 , 52 ]. For example, previous studies showed that clock genes have demonstrated a role of circadian rhythm in muscle atrophy and bone remodeling [ 53 , 54 , 55 ]. In addition, these clock genes have been implicated in NAFLD [ 56 ], the symptoms of which have been observed in mice during spaceflight [ 10 ].…”

Time-of-Day-Dependent Physiological Responses to Meal and Exercise

“…However, its mechanism remains unclear. In a recent animal study, it was reported that the preventive effects of stimulus like a rehabilitation on muscle atrophy depended on its timing (124). Intermittent weight-bearing for 4 h prevents the hindlimb-unloading-induced muscle atrophy and the up-regulation of Atrogin1 expression, which is one of the muscle catabolic genes (124,125).…”

“…In a recent animal study, it was reported that the preventive effects of stimulus like a rehabilitation on muscle atrophy depended on its timing (124). Intermittent weight-bearing for 4 h prevents the hindlimb-unloading-induced muscle atrophy and the up-regulation of Atrogin1 expression, which is one of the muscle catabolic genes (124,125). These preventive effects are greater in mice, which perform weightbearing in the early active phase compared with weight-bearing in the late period of active phase (equivalent to evening in human because mice are nocturnal) (124).…”

“…Intermittent weight-bearing for 4 h prevents the hindlimb-unloading-induced muscle atrophy and the up-regulation of Atrogin1 expression, which is one of the muscle catabolic genes (124,125). These preventive effects are greater in mice, which perform weightbearing in the early active phase compared with weight-bearing in the late period of active phase (equivalent to evening in human because mice are nocturnal) (124). In addition, these preventive effects of weight-bearing at the early active phase are not observed in the Clock mutant mice, suggesting that the effects of rehabilitation time is mediated via the circadian clock protein CLOCK (124).…”

“…These preventive effects are greater in mice, which perform weightbearing in the early active phase compared with weight-bearing in the late period of active phase (equivalent to evening in human because mice are nocturnal) (124). In addition, these preventive effects of weight-bearing at the early active phase are not observed in the Clock mutant mice, suggesting that the effects of rehabilitation time is mediated via the circadian clock protein CLOCK (124). From these reports, it is possible that the beneficial timing of exercise is different by your aim.…”