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

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. Specialised 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 synthesise 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 specialisation 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. 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 from a given myonucleus, as well as the proteins that are made from them, are actively transported along microtubule ‘tracks’ in adult muscle. Myonuclei can also move along tracks using molecular motors to facilitate specialised gen