Skeletal Muscle Stem Cell-Derived Myonuclei Adopt Divergent Terminal Transcriptional States in Adult and Aged Muscle In Response to a Hypertrophic Stimulus

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Summary Skeletal muscle stem cells (MuSCs) give rise to a fusogenic cell population that provide new myonuclei to muscle fibers. Myonuclear functional heterogeneity has recently become appreciated, but the terminal identity of MuSC-Derived myonuclei remains undefined. We performed single-nucleus RNA-sequencing of myonuclei in Adult and Aged muscle to define MuSC-Derived and resident myonuclear responses to mechanical overload (MOV), which induces a hypertrophic stimulus. We found a MuSC-dependent induction of a youthful transcriptional signature in resident myonuclei after MOV in Aged muscle. Age determined terminal transcriptional states of MuSC-Derived myonuclei toward MTJ in Adult, NMJ in Aged, and muscle spindles in both ages. Microtubule-remodeling genes, Macf1 , Map1b , and Nav3 , along with the transcription factor Runx1 , identified this post-fusion specialization with greater expression of these genes in Adult than in Aged MuSC-Derived myonuclei. In-silico transcription factor KO screen identified Runx1 as a regulator of post-fusion specialization and Esrrg as a driver of spindle (intrafusal) MuSC-Derived myonuclear maturation. By defining the age-associated fate of MuSC fusion to muscle fibers, we provide potential targets for modulating muscle plasticity. Highlights MuSC presence creates a more youthful myonuclear transcriptional signature in Aged muscle with mechanical overload (MOV). MOV-Responsive myonuclei depend on MuSCs in Aged but not Adult skeletal muscle MuSC-Derived myonuclei transcriptionally specialize to support the myotendinous junction in Adult muscle, the neuromuscular junction in Aged muscle, and muscle spindle (intrafusal) fibers in both ages. Pseudotime predicts Runx1 may function as a master regulator of MuSC-Derived myonuclear specialization in response to MOV.

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