Skeletal Muscle Nuclei in Mice are not Post-mitotic.

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.