Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Nat Commun. 2024 Oct 30;15(1):9372. doi: 10.1038/s41467-024-53510-z.
Multinucleated skeletal muscle cells 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 cells that already harbor hundreds of nuclei. Here we utilize nuclear RNA-sequencing approaches and develop 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.
多核骨骼肌细胞在响应发育和适应性生长刺激时，需要通过与激活的骨骼肌干细胞融合来获得额外的核。骨骼肌生物学中的一个基本问题是，对于已经拥有数百个核的细胞来说，为什么需要新的核。在这里，我们利用核 RNA 测序方法和开发了一种谱系追踪策略，能够定义最近融合核的转录状态，并将其与预先存在的核的状态区分开来。我们的研究结果揭示了在发育过程中和成年后肥大刺激期间新融合核中保守标记物的存在。然而，新融合的核也表现出不同的基因表达，这是由它们融合的成肌环境决定的。此外，通过融合获得新核对于已经存在于成年肌纤维中的核来说，对于负荷诱导刺激产生正常的转录反应是必需的。我们提出了一个关于骨骼肌发育和适应控制的相互调节模型，其中新融合和预先存在的肌核群体相互影响，以维持最佳的功能生长。
