Lineage tracing of newly accrued nuclei in skeletal myofibers uncovers distinct transcripts and interplay between nuclear populations.
Lineage tracing of newly accrued nuclei in skeletal myofibers uncovers distinct transcripts and interplay between nuclear populations.
复制标题
骨骼肌纤维中新产生的细胞核的谱系追踪揭示了不同的转录本和细胞核群体之间的相互作用。
DOI：
10.1101/2023.08.24.554609
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Millay,DouglasP
中科院分区：
文献类型：
--
作者：
Sun,Chengyi;Swoboda,CaseyO;Petrany,MichaelJ;Parameswaran,Sreeja;VonHandorf,Andrew;Weirauch,MatthewT;Lepper,Christoph;Millay,DouglasP
多核骨骼肌细胞在对发育和适应性生长刺激做出反应时，必须通过与活化的骨骼肌干细胞融合来获得额外的细胞核。骨骼肌生物学中的一个基本问题是，在已经拥有数百个细胞核的合胞体细胞中需要新细胞核的原因。为了开始回答这个长期存在的问题，我们利用核RNA测序方法并开发了一种谱系追踪策略，该策略能够定义最近融合的核的转录状态并将该状态与预先存在的核的转录状态区分开。我们的研究结果揭示了新融合的核在发展过程中和成人肥大刺激后的保守标记的存在。然而，新融合的细胞核也表现出不同的基因表达，这是由它们融合的肌源性环境决定的。此外，通过融合的新细胞核的积累是必需的细胞核已经驻留在成人肌纤维安装一个正常的转录反应的负荷诱导刺激。我们提出了一个模型，在控制骨骼肌的发育和适应，新融合和预先存在的肌群相互影响，以保持最佳的功能增长的相互调节。
Multinucleated skeletal muscle cells have an obligatory need to acquire additional nuclei through fusion with activated skeletal muscle stem cells when responding to both developmental and adaptive growth stimuli. A fundamental question in skeletal muscle biology has been the reason underlying this need for new nuclei in syncytial cells that already harbor hundreds of nuclei. To begin to answer this long-standing question, we utilized nuclear RNA-sequencing approaches and developed a lineage tracing strategy capable of defining the transcriptional state of recently fused nuclei and distinguishing this state from that of pre-existing nuclei. Our findings reveal the presence of conserved markers of newly fused nuclei both during development and after a hypertrophic stimulus in the adult. However, newly fused nuclei also exhibit divergent gene expression that is determined by the myogenic environment to which they fuse. Moreover, accrual of new nuclei through fusion is required for nuclei already resident in adult myofibers to mount a normal transcriptional response to a load-inducing stimulus. We propose a model of mutual regulation in the control of skeletal muscle development and adaptations, where newly fused and pre-existing myonuclear populations influence each other to maintain optimal functional growth.