Skeletal muscle fibers count on nuclear numbers for growth - PubMed (original) (raw)
Review
Skeletal muscle fibers count on nuclear numbers for growth
Vikram Prasad et al. Semin Cell Dev Biol. 2021 Nov.
Abstract
Skeletal muscle cells are noteworthy for their syncytial nature, with each myofiber accumulating hundreds or thousands of nuclei derived from resident muscle stem cells (MuSCs). These nuclei are accrued through cell fusion, which is controlled by the two essential fusogens Myomaker and Myomerger that are transiently expressed within the myogenic lineage. While the absolute requirement of fusion for muscle development has been known for decades, the underlying need for the magnitude of multinucleation in muscle remains mysterious. Possible advantages of multinucleation include the potential it affords for transcriptional diversity within these massive cells, and as a means of increasing DNA content to support optimal cell size and function. In this article, we review recent advances that elucidate the relationship between myonuclear numbers and establishment of myofiber size, and discuss how this new information refines our understanding of the concept of myonuclear domains (MND), the cytoplasmic volumes that each resident myonucleus can support. Finally, we explore the potential consequences and costs of multinucleation and its impacts on myonuclear transcriptional reserve capacity, growth potential, myofiber size regulation, and muscle adaptability. We anticipate this report will not only serve to highlight the latest advances in the basic biology of syncytial muscle cells but also provide information to help design the next generation of therapeutic strategies to maintain muscle mass and function.
Keywords: Cell fusion; Multinucleation; Myonuclear domain; Skeletal muscle size; Transcriptional output.
Copyright © 2021. Published by Elsevier Ltd.
Figures
Fig. 1.. Relationship between myonuclear content, myonuclear domain and growth in syncytial myofibers.
Each resident myonucleus supports a finite volume of cellular content called its myonuclear domain (MND), which reflects its biosynthetic capacity. The sum total of all MND volumes within a myofiber dictates a theoretical ceiling on the size it can potentially achieve, termed baseline MND ceiling (dashed red line). (A) In myofibers with large MNDs myofiber baseline size (left panel) approximates this ceiling with resident myonuclear biosynthetic capacity posited to be fully utilized. Adaptive growth in response to increased workload (right panel) in such myofibers requires accrual of new myonuclei (blue nuclei) and is therefore generated by increasing MND numbers. The baseline MND ceiling gets reset at a higher level (not depicted). (B) In myofibers with smaller MNDs, baseline size (left panel) is maintained below the MND ceiling, which leaves reserve potential (red arrows) to be utilized for growth during increased workload. In these fibers, myonuclear accrual is therefore not essential for adaptive growth, which is generated, at least initially, by increasing pre-existing MND sizes and not MND numbers. (C) Titration of myonuclear numbers in mice has revealed the existence of a myonuclear transcriptional reserve capacity to support MNDs much larger than typically generated in normal adult myofibers. The magnitude of reserve capacity elicited correlates with mRNA concentrations and is inversely related to myonuclear content. It progressively diminishes as myonuclear numbers approach normal, control levels. This inverse relationship could explain limits in myonuclear biosynthetic capacities and the roles of MND volumes, ceilings, and plasticity in the generation of adaptive growth in adult myofibers.
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