Skeletal Muscle Nuclei in Mice are not Post-mitotic

Author:

Borowik Agnieszka K1,Davidyan Arik12ORCID,Peelor Frederick F1,Voloviceva Evelina1ORCID,Doidge Stephen M1,Bubak Matthew P1,Mobley Christopher B3,McCarthy John J45,Dupont-Versteegden Esther E456,Miller Benjamin F17ORCID

Affiliation:

1. Aging and Metabolism Research Program, Oklahoma Medical Research Foundation , 825 NE 13th St, Oklahoma City, OK 73104 , USA

2. Department of Biological Sciences, California State University Sacramento , 6000 J Street, Sacramento, CA, 95819 , USA

3. School of Kinesiology, Auburn University , 301 Wire Rd, Auburn, AL 36849 , USA

4. Center for Muscle Biology, University of Kentucky , Lexington, KY 40506 , USA

5. Department of Physiology, College of Medicine, University of Kentucky , Lexington, KY, 40506 , USA

6. Department of Physical Therapy, College of Health Sciences, University of Kentucky , 900 S Limestone, Lexington, KY 40536 , USA

7. Oklahoma City VA Medical Center , 921 NE 13th St, Oklahoma City, OK 73104 , USA

Abstract

Abstract The skeletal muscle research field generally accepts that nuclei in skeletal muscle fibers (ie, myonuclei) are post-mitotic and unable to proliferate. Because our deuterium oxide (D2O) labeling studies showed DNA synthesis in skeletal muscle tissue, we hypothesized that resident myonuclei can replicate in vivo. To test this hypothesis, we used a mouse model that temporally labeled myonuclei with GFP followed by D2O labeling during normal cage activity, functional overload, and with satellite cell ablation. During normal cage activity, we observed deuterium enrichment into myonuclear DNA in 7 out of 7 plantaris (PLA), 6 out of 6 tibialis anterior (TA), 5 out of 7 gastrocnemius (GAST), and 7 out of 7 quadriceps (QUAD). The average fractional synthesis rates (FSR) of DNA in myonuclei were: 0.0202 ± 0.0093 in PLA, 0.0239 ± 0.0040 in TA, 0.0076 ± 0. 0058 in GAST, and 0.0138 ± 0.0039 in QUAD, while there was no replication in myonuclei from EDL. These FSR values were largely reproduced in the overload and satellite cell ablation conditions, although there were higher synthesis rates in the overloaded PLA muscle. We further provided evidence that myonuclear replication is through endoreplication, which results in polyploidy. These novel findings contradict the dogma that skeletal muscle nuclei are post-mitotic and open potential avenues to harness the intrinsic replicative ability of myonuclei for muscle maintenance and growth.

Funder

National Institutes of Health

EDV

MPB

Department of Veteran Affairs

Publisher

Oxford University Press (OUP)

Subject

General Medicine

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