Nuclear numbers in syncytial muscle fibers promote size but limit the development of larger myonuclear domains

Author:

Cramer Alyssa A. W.ORCID,Prasad Vikram,Eftestøl EinarORCID,Song Taejeong,Hansson Kenth-Arne,Dugdale Hannah F.,Sadayappan SakthivelORCID,Ochala JulienORCID,Gundersen Kristian,Millay Douglas P.ORCID

Abstract

AbstractMammalian cells exhibit remarkable diversity in cell size, but the factors that regulate establishment and maintenance of these sizes remain poorly understood. This is especially true for skeletal muscle, comprised of syncytial myofibers that each accrue hundreds of nuclei during development. Here, we directly explore the assumed causal relationship between multinucleation and establishment of normal size through titration of myonuclear numbers during mouse neonatal development. Three independent mouse models, where myonuclear numbers were reduced by 75, 55, or 25%, led to the discovery that myonuclei possess a reserve capacity to support larger functional cytoplasmic volumes in developing myofibers. Surprisingly, the results revealed an inverse relationship between nuclei numbers and reserve capacity. We propose that as myonuclear numbers increase, the range of transcriptional return on a per nuclear basis in myofibers diminishes, which accounts for both the absolute reliance developing myofibers have on nuclear accrual to establish size, and the limits of adaptability in adult skeletal muscle.

Funder

U.S. Department of Health & Human Services | NIH | National Institute on Aging

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases

Pew Biomedical Scholar

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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