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Updated: Aug 16, 2025
Exploiting Live Imaging to Track Nuclei During Myoblast Differentiation and Fusion
Published on: April 13, 2019
Skeletal Muscle Nuclei in Mice are not Post-mitotic
Agnieszka K Borowik1, Arik Davidyan1,2, Frederick F Peelor1
1Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma City, OK 73104, USA.
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.
Insights
Skeletal muscle nuclei, previously thought unable to divide, can replicate in vivo. This discovery challenges existing dogma and suggests new ways to promote muscle repair and growth.
Area of Science:
- Skeletal Muscle Physiology
- Cell Biology
- Molecular Biology
Background:
- The prevailing view in skeletal muscle research is that myonuclei are post-mitotic and lack proliferative capacity.
- Recent deuterium oxide (D2O) labeling studies indicated DNA synthesis within skeletal muscle tissue.
Purpose of the Study:
- To investigate the hypothesis that resident myonuclei possess the ability to replicate in vivo.
- To challenge the established dogma of post-mitotic myonuclei in skeletal muscle.
Main Methods:
- Utilized a mouse model with temporal myonuclear labeling using Green Fluorescent Protein (GFP).
- Administered D2O labeling during normal cage activity, functional overload, and satellite cell ablation.
- Quantified DNA synthesis via fractional synthesis rates (FSR) in various skeletal muscles.
Main Results:
- Observed deuterium enrichment in myonuclear DNA across multiple skeletal muscles (Plantaris, Tibialis Anterior, Gastrocnemius, Quadriceps) during normal activity.
- Calculated significant fractional synthesis rates (FSR) for DNA in myonuclei, indicating replication.
- Replication rates were largely consistent across experimental conditions, with increased synthesis in overloaded Plantaris muscle.
- Provided evidence that myonuclear replication occurs via endoreplication, leading to polyploidy.
Conclusions:
- Demonstrated that myonuclei in skeletal muscle fibers can replicate in vivo, contradicting the long-held belief of their post-mitotic nature.
- These findings suggest novel therapeutic strategies for muscle maintenance and hypertrophy by leveraging the intrinsic replicative potential of myonuclei.
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