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

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. 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.

Effects of high‐resistance wheel running on hallmarks of endurance and resistance training adaptations in mice

“…Whether the increase in mass translates into higher force production of the M. soleus in any or both of the training modalities remains to be tested. Moreover, whether Run and RR differentially affect satellite cell activation and myonuclear accretion, both important aspects in resistance training adaptation (Bagley et al, 2023 ), has to be addressed in future studies. However, the proteomic signatures of trained M. soleus and M. plantaris exhibited differences, and in both muscles, low‐ and high‐resistance wheel running have elicited distinct adaptations.…”

Automated in‐depth fiber and nuclei typing in cross‐sectional muscle images can pave the way to a better understanding of skeletal muscle diseases

“…The distribution of myonuclei within the muscle fiber plays an essential role in their supply and regulation, 16 but mechanisms for their motility, increase, and degradation are poorly understood to date. 16 Since nucleotyping can clearly specify statements about the health status of a muscle in addition to fiber typing, the search for a specific marker has been the subject of research for some time. The protein pericentriolar material 1 has been shown to be a specific marker of post-mitotic myonuclei.…”

“…By incorporating another deep learning algorithm, nucleAIzer, 15 the detection of nuclei itself in FiNuTyper 1 is further improved. The distribution of myonuclei within the muscle fiber plays an essential role in their supply and regulation, 16 but mechanisms for their motility, increase, and degradation are poorly understood to date 16 . Since nucleotyping can clearly specify statements about the health status of a muscle in addition to fiber typing, the search for a specific marker has been the subject of research for some time.…”

Muscle fibre size and myonuclear positioning in trained and aged humans

“…The myonuclear domain (MND) volume is the theoretical volume of cytoplasm for which a myonucleus is responsible (Allen et al, 1999 ). Changes in the architecture, number and organization of myonuclei and in MND size have been associated with muscle adaptation, including adaptation in response to exercise training, injury, disuse, disease and ageing (Bagley et al., 2023 ; Battey et al., 2023 , 2020 ; Mohiuddin et al., 2019 ; Murach et al, 2020 ; Stroud et al., 2017 ). However, data on changes in MND size and myonuclear arrangement following exercise are inconsistent (Abreu et al., 2017 ; Verney et al., 2008 ).…”