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Lineage tracing of newly accrued nuclei in skeletal myofibers uncovers distinct transcripts and interplay between nuclear populations

ABSTRACT: Multinucleated skeletal muscle cells have an obligatory need to acquire additional nuclei through fusion with activated skeletal muscle stem cells when responding to both developmental and adaptive growth stimuli. A fundamental question in skeletal muscle biology has been the reason underlying this need for new nuclei in syncytial cells that already harbor hundreds of nuclei. To begin to answer this long-standing question, we utilized nuclear RNA-sequencing approaches and developed a lineage tracing strategy capable of defining the transcriptional state of recently fused nuclei and distinguishing this state from that of pre-existing nuclei. Our findings reveal the presence of conserved markers of newly fused nuclei both during development and after a hypertrophic stimulus in the adult. However, newly fused nuclei also exhibit divergent gene expression that is determined by the syncytial environment they fuse into. Moreover, accrual of additional nuclei through fusion is required for nuclei already resident in adult myofibers to mount a normal transcriptional response to a load-induced stimulus. We propose a model of mutual regulation in the control of skeletal muscle development and adaptations, where newly fused and pre-existing myonuclei influence each other to maintain optimal functional growth.

ORGANISM(S): Mus musculus

PROVIDER: GSE241035 | GEO | 2023/08/23

REPOSITORIES: GEO

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Project description:Methods for studying mitochondrial adaptations in skeletal muscle have mostly used whole-muscle samples, where results may be confounded by the presence of a mixture of type I and II skeletal muscle fibres. In this project, we utilised the latest Mass spectrometry (MS) techniques to provide new insights into mitochondrial adaptations in type I and II fibres in response to two different types of training – moderate-intensity-continuous training (MICT) and sprint-interval training (SIT). An 8-week training intervention was undertaken by 23 men who performed either MICT or SIT. Single muscle fibres from skeletal muscle biopsies were collected at rest, before and after the 8 weeks of training, and pooled for subsequent MS analysis. A proteomic workflow was applied that permitted a three-tiered comparison and quantification of mitochondrial proteins in different fibre types. Our protocol includes tandem mass tag labelling for increased identification of low-abundant proteins. We quantified more than 45% of known mitochondrial proteins in skeletal muscle. When comparing type I to type II fibres,24 mitochondrial proteins were differentially expressed following MICT and 10 following SIT. These altered proteins were associated with known cellular pathways within the mitochondria, including oxidative phosphorylation, the TCA cycle and fatty acid oxidation. There were distinct trends for fibre-type-specific protein responses to different types of exercise training. Following MICT proteins mostly increased in abundance in type I fibres, without analogous changes observed following SIT. This greater upregulation of mitochondrial proteins observed following MICT, suggests exercise volume is a powerful stimulus for mitochondrial adaptations. This upregulation mostly seen in type I fibres is consistent with the predominate recruitment of this fibre type with MICT. When normalised to mitochondrial content further evidence to fibre-specific non-stoichiometrically induced increases in the expression of fatty acid mitochondrial proteins is presented, highlighting mitochondria as a pivotal subcellular site in facilitating substrate utilisation to increase ATP production in type I fibres. Conversely, the research suggests very high-intensity exercise training altered the systematic biogenesis of oxidative phosphorylation (OXPHOS) components, in particular complex IV subunits of the OXPHOS pathway. These results question the existing knowledge of fibre-type-specific changes to mitochondrial proteins in response to exercise training and provide a valuable contribution to understanding the mechanisms by which exercise helps to improve health and prevent disease.

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Lineage tracing of newly accrued nuclei in skeletal myofibers uncovers distinct transcripts and interplay between nuclear populations

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