Department of Nutrition, Food and Exercise Sciences, Florida State University, Tallahassee, Florida.
Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida.
Am J Physiol Endocrinol Metab. 2019 Oct 1;317(4):E631-E645. doi: 10.1152/ajpendo.00177.2019. Epub 2019 Jul 30.
Androgen depletion in humans leads to significant atrophy of the limb muscles. However, the pathways by which androgens regulate limb muscle mass are unclear. Our laboratory previously showed that mitochondrial degradation was related to the induction of autophagy and the degree of muscle atrophy following androgen depletion, implying that decreased mitochondrial quality contributes to muscle atrophy. To increase our understanding of androgen-sensitive pathways regulating decreased mitochondrial quality, total RNA from the tibialis anterior of sham and castrated mice was subjected to microarray analysis. Using this unbiased approach, we identified significant changes in the expression of genes that compose the core molecular clock. To assess the extent to which androgen depletion altered the limb muscle clock, the tibialis anterior muscles from sham and castrated mice were harvested every 4 h throughout a diurnal cycle. The circadian expression patterns of various core clock genes and known clock-controlled genes were disrupted by castration, with most genes exhibiting an overall reduction in phase amplitude. Given that the core clock regulates mitochondrial quality, disruption of the clock coincided with changes in the expression of genes involved with mitochondrial quality control, suggesting a novel mechanism by which androgens may regulate mitochondrial quality. These events coincided with an overall increase in mitochondrial degradation in the muscle of castrated mice and an increase in markers of global autophagy-mediated protein breakdown. In all, these data are consistent with a novel conceptual model linking androgen depletion-induced limb muscle atrophy to reduced mitochondrial quality control via disruption of the molecular clock.
在人类中，雄激素的耗竭会导致肢体肌肉明显萎缩。然而，雄激素调节肢体肌肉质量的途径尚不清楚。我们实验室之前的研究表明，线粒体的降解与自噬的诱导以及雄激素耗竭后肌肉萎缩的程度有关，这意味着线粒体质量的下降导致了肌肉萎缩。为了更深入地了解雄激素敏感途径调节线粒体质量下降的机制，我们对假手术组和去势组小鼠的胫骨前肌总 RNA 进行了微阵列分析。使用这种无偏的方法，我们确定了构成核心分子钟的基因表达的显著变化。为了评估雄激素耗竭对肢体肌肉时钟的影响程度，我们在一个昼夜周期内每隔 4 小时从假手术组和去势组小鼠中采集胫骨前肌。各种核心时钟基因和已知的时钟控制基因的昼夜节律表达模式被去势破坏，大多数基因的相位幅度总体降低。由于核心时钟调节线粒体质量，时钟的破坏与参与线粒体质量控制的基因表达的变化相吻合，这表明雄激素可能调节线粒体质量的一种新机制。这些事件与去势小鼠肌肉中线粒体降解的总体增加以及参与全局自噬介导的蛋白质降解的标志物的增加同时发生。总之，这些数据与一种新的概念模型一致，该模型将雄激素耗竭诱导的肢体肌肉萎缩与通过破坏分子钟导致的线粒体质量控制降低联系起来。
