![]() Some myoblasts continue to proliferate while others commit to differentiation ( Relaix and Zammit, 2012). ![]() For both mice and humans, quiescent satellite cells expressing Pax7 become activated, express Myod and proliferate ( Figure 1) ( Zanou and Gailly, 2013). Regeneration is stimulated upon injury when satellite cells become activated ( Zanou and Gailly, 2013). Myogenesis in adult muscle follows a similar trajectory as seen in development. Satellite cells reside under the basal lamina in direct contact with the myofiber ( Chal and Pourquié, 2017). Each individual myofiber is surrounded by a matrix of connective proteins termed the basal lamina ( Schiaffino and Reggiani, 2011). Several myofibers group together to form fascicles, and multiple fascicles make up the total muscle ( Jorgenson et al., 2020). At this point, the satellite cells also become quiescent, and muscle structure is established ( Relaix and Zammit, 2012 Chal and Pourquié, 2017). Myoblasts continue to fuse to myofibers after birth to build the muscle until postnatal day 21 in mice ( Relaix and Zammit, 2012). The major muscle specification and patterning is complete at this point ( Huang, 2017). Following Myog expression at day E11.5 in mouse, Mrf4 (herculin/Myf6) is turned on at day E13.5 and controls final myofiber structure such as myonuclear positioning ( Huang, 2017). Satellite cells become activated in embryogenesis by turning on Myod and turning off Pax7 to form myoblasts which fuse to existing myofibers ( Relaix and Zammit, 2012 Chal and Pourquié, 2017). Pax7+ cells that do not fuse will continue to cycle and become satellite cells ( Figure 1) ( Chal and Pourquié, 2017). These cells either fuse to each other forming new myotubes or to the primary fibers by turning on the transcription factor Myod and then Myog ( Chal and Pourquié, 2017). After the formation of these primary fibers, remaining cycling cells downregulate Pax3 and upregulate Pax7 ( Chal and Pourquié, 2017). The muscle regulatory factors (MRFs) Myf5, Myod, Mrf4 and Myog control the transition from cycling to postmitotic cells that go on to form primary fibers ( Chal and Pourquié, 2017). Skeletal muscle is initially specified in embryonic development when the somite segments into the dermomyotome, and muscle specification begins with the expression of transcriptional regulators Pax3 and Myf5 around embryonic day 9 (E9) in mouse ( Chal and Pourquié, 2017). Muscle differentiation and fusion, called myogenesis, is controlled by a gene regulatory network well studied in mice ( Blais, 2015 Chal and Pourquié, 2017). Myofibers can reach up to 30 cm in length in humans and 10 mm in mice and have hundreds of nuclei ( Konno and Suzuki, 2000 Griffin et al., 1971). Adult skeletal muscle tissue is composed primarily of mature muscle cells called myofibers and undifferentiated muscle cells called satellite cells. Skeletal muscle is the most abundant tissue in our bodies and is crucial for voluntary movement and support. Disease-specific nucleus populations were found in two muscular dystrophies, FSHD and Duchenne muscular dystrophy, demonstrating the importance of performing transcriptome studies at the single nucleus level in muscle. We summarize the major myonuclei subtypes identified in homeostatic and regenerating tissue including those specific to fiber type or at junctions with other cell types. We survey current methods of high-throughput single cell and subcellular resolution transcriptomics, including single-cell and single-nucleus RNA-seq and spatial transcriptomics, applied to satellite cells, myoblasts, myotubes and myofibers. Nuclear heterogeneity plays important roles in certain diseases such as muscular dystrophies. Nuclei within myofibers specialize at junctions with other cell types such as motor neurons. For the study of muscle, single-nucleus RNA-seq (snRNA-seq) has emerged not only as an alternative to scRNA-seq, but as a novel method providing valuable insights into multinucleated cells such as myofibers. Single-cell RNA-seq (scRNA-seq) has revolutionized modern genomics, but the large size of myotubes and myofibers has restricted use of scRNA-seq in skeletal muscle. 3Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, United States.2Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, United States.1Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, United States.Katherine Williams 1,2* Kyoko Yokomori 3 Ali Mortazavi 1,2*
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