The myonuclear domain in adult skeletal muscle fibres: Past, present, and future.

Various mechanisms and conditions contribute to regulation of the "myonuclear domain", or theoretically finite area that an individual myoncleus provides gene products to within a multinuclear muscle fiibre mRNA from an individual myonucleus and the protein it produces are actively transported by molecular motors along microtubules in muscle fibres, as are myonuclei The distance that an mRNA or protein travels away from its myonucleus of origin is variable based on a variety of known and unknown factors Current evidence indicates that myonuclei are added during muscle hypertrophy fibre and lost during atrophy, perhaps to stabilize the myonuclear domain Myonuclei within a muscle fibre are transcriptionally and functionally diverse, which may have consequences for myonuclear domain maintenance and muscle fibre homeostasis ABSTRACT: Most cells in the body are mononuclear whereas skeletal muscle fibres are uniquely multinuclear. The nuclei of muscle fibres (myonuclei) are usually situated peripherally which complicates the equitable distribution of gene products. Myonuclear abundance can also change under conditions such as hypertrophy and atrophy. Specialized zones in muscle fibres have different functions and thus distinct synthetic demands from myonuclei. The complex structure and regulatory requirements of multinuclear muscle cells understandably led to the hypothesis that myonuclei govern defined "domains" to maintain homeostasis and facilitate adaptation. The purpose of this review is to provide historical context for the myonuclear domain and evaluate its veracity with respect to mRNA and protein distribution resulting from myonuclear transcription. We synthesize insights from past and current in vitro and in vivo genetically modified models for studying the myonuclear domain under dynamic conditions. We also cover the most contemporary knowledge on mRNA and protein transport in muscle cells. Insights from emerging technologies such as single myonuclear RNA-sequencing further inform our discussion of the myonuclear domain. We broadly conclude: 1) the myonuclear domain can be flexible during muscle fibre growth and atrophy, 2) the mechanisms and role of myonuclear loss and motility deserve further consideration, 3) mRNA in muscle is actively transported via microtubules and locally restricted, but proteins may travel far from a myonucleus of origin, and 4) myonuclear transcriptional specialization extends beyond the classic neuromuscular and myotendinous populations. A deeper understanding of the myonuclear domain in muscle may promote effective therapies for ageing and disease. Abstract figure legend The "myonuclear domain" is the theoretically finite area that an individual muscle fibre nucleus provides RNA for within the multinuclear cell. The myonuclear domain may only expand to a certain extent during muscle fibre growth (hypertrophy) before the addition of a new myonucleus from a muscle stem cell (satellite cell) is required. Conversely, the myonuclear domain may shrink during muscle atrophy and myonuclei may eventually be lost (top left panel). mRNAs, as well as the proteins that are made from them from a given myonucleus, are actively transported along microtubule "tracks" in adult muscle. Myonuclei can also move along tracks using molecular motors to facilitate specialized gene expression and protein synthesis where needed (top right panel). mRNAs and proteins from an individual myonucleus can travel different distances in the cell based on specific molecular characteristics as well as enviromental conditions (bottom left panel). Furthermore, myonuclear gene expression is specialized based on location in the cell (bottom right panel). Collectively, various mechanisms may influence the size of the myonuclear domain. Undertanding how the myonuclear domain is regulated and maintained has implications for muscle adaptation and the etiology of disease. This article is protected by copyright. All rights reserved.