mRNA transcription in skeletal muscle drives growth and determines nuclear accretion

Montecino-Morales, F.; Calvo, C.; Swoboda, C. O.; Bruening, A.; Cramer, A. A. W.; Lin, X.; Martin, J. L.; Khairallah, R. J.; Diao, Y.; Prasad, V.; Millay, D.

doi:10.64898/2025.12.29.696842

bioRxiv · 10.64898/2025.12.29.696842

mRNA transcription in skeletal muscle drives growth and determines nuclear accretion

Montecino-Morales, F.·Calvo, C.·Swoboda, C. O.·Bruening, A.·Cramer, A. A. W.·Lin, X.·Martin, J. L.·Khairallah, R. J.·Diao, Y.·Prasad, V.·Millay, D.

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Abstract

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 why myofibers need 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 for additional nuclei for myofiber growth. These data reveal a previously neglected driver of functional muscle growth and highlight that increasing Polr2a-mediated transcription from the vast numbers of nuclei within myofibers could be leveraged to combat muscle wasting conditions.

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Montecino-Morales, F., Calvo, C., Swoboda, C. O., Bruening, A., Cramer, A. A. W., Lin, X., Martin, J. L., Khairallah, R. J., Diao, Y., Prasad, V., Millay, D.. 2025-12-29. mRNA transcription in skeletal muscle drives growth and determines nuclear accretion. https://doi.org/10.64898/2025.12.29.696842

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