TFE3 在决定肌肉去神经后线粒体和溶酶体含量方面的二态效应

IF 5.3 2区 医学 Q2 CELL BIOLOGY
Ashley N. Oliveira, Jonathan M. Memme, Jenna Wong, David A. Hood
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引用次数: 0

摘要

肌肉萎缩是神经支配丧失的常见后果,并伴有线粒体功能障碍。线粒体吞噬是一个适应过程,受损的线粒体通过溶酶体被清除,而溶酶体在一定程度上受转录因子 TFE3 的调控。人们对溶酶体和 TFE3 在肌肉萎缩中的作用知之甚少,对生物性别的影响也普遍报道不足。对野生型(WT)小鼠和缺乏溶酶体和自噬相关基因转录调节因子 TFE3(KO)的小鼠进行长达 7 天的单侧坐骨神经去神经支配,同时对侧肢体进行假手术并作为内部对照。用秋水仙碱处理一部分动物,以捕捉有丝分裂通量。与雄性动物相比,WT雌性动物在活跃呼吸状态下表现出更高的耗氧率,但在没有TFE3的情况下,耗氧率会降低。与雄性小鼠相比,雌性小鼠表现出更高的有丝分裂通量率和更高的溶酶体含量,这与 TFE3 的表达无关。去神经支配后,雌性小鼠的肌肉萎缩程度低于雄性小鼠。耐人寻味的是,在没有 TFE3 的情况下,这种依赖于性别的肌肉疏松也会消失。去神经化导致 WT 雄性和 KO 雄性的线粒体含量分别减少了 45% 和 27%,而雌性则完全避免了线粒体含量的减少。去神经支配后,WT雌性线粒体功能的下降比雄性更严重,因为ROS排放量高出2.4倍。作为对去神经化的反应,雌性的 LC3-II 有丝分裂通量减少了 44%,这可能是维持线粒体含量和 ROS 释放量升高的原因之一,但在没有 TFE3 的情况下,这种反应会失调。虽然雄性和雌性在去神经化后都表现出溶酶体含量的增加,但这种反应在雌性中以依赖 TFE3 的方式增强。与雄性相比,雌性的溶酶体含量和有丝分裂通量较高,这可能是线粒体表型改善的原因。去神经诱导的线粒体适应具有性别二态性,因为雌性以牺牲功能为代价优先保存线粒体含量,而雄性则倾向于维持线粒体功能。我们的数据表明,TFE3 对于线粒体功能的性别差异以及决定去神经支配诱导的萎缩表型至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dimorphic effect of TFE3 in determining mitochondrial and lysosomal content in muscle following denervation
Muscle atrophy is a common consequence of the loss of innervation and is accompanied by mitochondrial dysfunction. Mitophagy is the adaptive process through which damaged mitochondria are removed via the lysosomes, which are regulated in part by the transcription factor TFE3. The role of lysosomes and TFE3 are poorly understood in muscle atrophy, and the effect of biological sex is widely underreported. Wild-type (WT) mice, along with mice lacking TFE3 (KO), a transcriptional regulator of lysosomal and autophagy-related genes, were subjected to unilateral sciatic nerve denervation for up to 7 days, while the contralateral limb was sham-operated and served as an internal control. A subset of animals was treated with colchicine to capture mitophagy flux. WT females exhibited elevated oxygen consumption rates during active respiratory states compared to males, however this was blunted in the absence of TFE3. Females exhibited higher mitophagy flux rates and greater lysosomal content basally compared to males that was independent of TFE3 expression. Following denervation, female mice exhibited less muscle atrophy compared to male counterparts. Intriguingly, this sex-dependent muscle sparing was lost in the absence of TFE3. Denervation resulted in 45% and 27% losses of mitochondrial content in WT and KO males respectively, however females were completely protected against this decline. Decreases in mitochondrial function were more severe in WT females compared to males following denervation, as ROS emission was 2.4-fold higher. In response to denervation, LC3-II mitophagy flux was reduced by 44% in females, likely contributing to the maintenance of mitochondrial content and elevated ROS emission, however this response was dysregulated in the absence of TFE3. While both males and females exhibited increased lysosomal content following denervation, this response was augmented in females in a TFE3-dependent manner. Females have higher lysosomal content and mitophagy flux basally compared to males, likely contributing to the improved mitochondrial phenotype. Denervation-induced mitochondrial adaptations were sexually dimorphic, as females preferentially preserve content at the expense of function, while males display a tendency to maintain mitochondrial function. Our data illustrate that TFE3 is vital for the sex-dependent differences in mitochondrial function, and in determining the denervation-induced atrophy phenotype.
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来源期刊
Skeletal Muscle
Skeletal Muscle CELL BIOLOGY-
CiteScore
9.10
自引率
0.00%
发文量
25
审稿时长
12 weeks
期刊介绍: The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.
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