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Whole-body replacement mechanism generates adult muscle tissues in the zebrafish model|Institute of Cellular and Organismic Biology, Academia Sinica


Whole-body replacement mechanism generates adult muscle tissues in the zebrafish model

Certain insects, such as beetles and butterflies, can undergo extensive tissue replacement during their developmental process, a transformation process considered unique to insects. Dr. Chen-Hui Chen and his team at the Institute of Cellular and Organismic Biology (ICOB) have developed a multicolor cell-barcoding technique to study the collective behavior of muscle cells in zebrafish. They found that zebrafish, as a vertebrate model, can similarly undergo complete muscle elimination and replacement during post-embryonic development. This unexpected finding was published in June this year in the EMBO J. 

Throughout the developmental process, animals adjust to different physiological demands by utilizing organs and tissues with varying functions at different stages. The metamorphosis of butterflies is one of the most classic examples: during the larval stage, they focus on growth, while during the adult stage, they focus on reproduction. The organs and tissues required at these two stages are vastly different, leading to extensive tissue breakdown and replacement throughout development. Compared to insects, vertebrates exhibit relatively limited changes in appearance during post-embryonic development. Nonetheless, at the cellular level, whether similar drastic changes occur akin to those observed in insect development remains an unexplored research topic. 

Here the team created the palmuscle myofiber tagging and tracking system for in toto monitoring of the growth and fates of ~5000 fast myofibers in developing zebrafish larvae. Uday Kumar, a graduate student in Dr. Chen’s laboratory, found that most if not all of the larval myofibers are eventually eliminated and replaced by adult counterparts, each possessing distinct morphologies, functions and lifespans. Mechanistically, they determined that cell-autonomous activation of autophagic cell death is both necessary and sufficient for the elimination and the subsequent new myofiber birth at the voided sites. All together, they propose that zebrafish successively grow two complete sets of fast myofiber populations, i.e., the larval myofibers that serve as a temporary set and the permanent set of adult myofibers. They speculate that the wholesale swap of early-born myofibers could be a common occurrence in vertebrate models. 

Dr. Chen noted that due to limitations in research tools, past studies on vertebrate muscle cells have primarily focused on cell culture models or histological investigations. This study may represent the first instance of simultaneously and continuously observing all muscle cells within an individual at both the organismal and cellular levels. Since the conclusions challenge the current understanding of vertebrate development, they repeatedly received polarized comments during the peer review process. From initial submission to final acceptance, the process spanned well over a year and a half. "Receiving anonymous reviewer comments each time felt like riding a roller coaster." Another aspect of this research finding is that it sparks contemplation on the distance between science and philosophy. Considering muscle cells as the primary units in vertebrates, if the majority of cells in an individual undergo complete replacement during development, can the individual before and after replacement still be regarded as the same entity? If so, none of the cells are original; if not, when does it cease being the same? "Intriguingly, analogies to the Ship of Theseus can help explaining the developmental mechanism of vertebrates. “

The first author, Uday Kumar, is affiliated with the Taiwan International Graduate Program, jointly administered by Academia Sinica and National Chung-Hsing University. Other team members include Chun-Yi Fang, Hsiao-Yuh Roan, Shao-Chun Hsu, Chung-Han Wang, and Chen-Hui Chen. This study is supported by funding from the Institute of Cellular and Organismic Biology and grants from Academia Sinica to C.-H.C. (AS-CDA-109-L03 and AS-GCS-112-L01); and grants from National Science and Technology Council, Taiwan, to C.-H.C. (NSTC 110-2628-B-001-016, and NSTC 111-2628-B-001-026). 


Magnified view of trunk myofibers in a live zebrafish.