Adaptive changes in the DNA damage response during skeletal muscle cell differentiation

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• The DNA damage response (DDR) is crucial for maintaining genomic stability.
• While well-studied in proliferating cells, the DDR in differentiated, postmitotic cells remains poorly understood.
• Skeletal muscle cells, as differentiated cells, have unique DDR requirements.

Purpose of the Study:

• To investigate the dynamics and mechanisms of the DDR during human skeletal muscle cell differentiation.
• To understand how differentiated muscle cells handle DNA double-strand breaks (DSBs).
• To elucidate the role of DDR in preserving genetic information in long-term organ function.

Main Methods:

• Established an *in vitro* differentiation model of human skeletal muscle myoblasts into myotubes.
• Utilized live-cell microscopy to monitor DDR dynamics.
• Employed single-molecule kinetic measurements to assess transcriptional activity.

Main Results:

• Differentiated myotubes exhibit a prolonged DDR compared to myoblasts.
• Myotubes demonstrate competence in repairing DSBs, leading to increased resistance to cell death.
• DNA damage triggers rapid, transient suppression of global gene expression in myotubes.
• The epigenetic landscape of the damaged nucleus is remodeled during the DDR in myotubes.

Conclusions:

• Human skeletal muscle cells employ a distinct DDR strategy during differentiation.
• This strategy involves a prolonged response, gene expression modulation, and epigenetic rewiring.
• These mechanisms are vital for maintaining genetic integrity and ensuring long-term skeletal muscle function.