mRNA transcription in skeletal muscle drives growth and determines nuclear accretion

Multinucleation of skeletal muscle cells (myofibers) is a determinant of size and fundamental for function. While it is established that myofibers need to accrue adequate numbers of nuclei for optimal growth, the molecular circuitry linking myonuclei to growth and how myofibers signal the need for additional nuclei remains unknown. We found that growth is still possible after restriction of nuclear content in myofibers and this was associated with increased levels of RNA Polymerase II (Polr2a) leading to elevated mRNA content. Through development of a genetic mouse model where endogenous Polr2a is upregulated in myofibers, we established that increased transcriptional output is sufficient to drive functional growth of myofibers. Notably, we discovered that Polr2a overexpression curtails the need of additional nuclei for myofiber growth. These data highlight a previously neglected mechanism for functional muscle growth through increasing Polr2a-mediated transcription from the vast numbers of nuclei within myofibers, which could be leveraged to combat muscle wasting conditions. Overall design: scATAC-Seq: Isolated nuclei from wild-type (n=3) and D2W(n=4) mice.