The Evolutionarily Conserved TPM1 Super-Enhancer Drives Skeletal Muscle Regeneration via Mechanotransduction...

Area of Science:

• Epigenetics
• Muscle Biology
• Mechanobiology

Background:

• Super-enhancers (SEs) are key epigenetic regulators in tissue regeneration.
• The interplay between SEs and cellular biomechanics in muscle regeneration is not well understood.
• The TPM1 gene, vital for skeletal muscle regeneration, contains a conserved SE (TPM1_SE).

Purpose of the Study:

• To investigate the role of TPM1_SE in myogenic differentiation and muscle regeneration.
• To elucidate the molecular mechanisms linking TPM1_SE to biomechanics and signaling pathways.
• To explore the therapeutic potential of TPM1_SE in regenerative medicine and livestock.

Main Methods:

• In vitro studies involving SE deletion and gene expression analysis.
• Conditional deletion of TPM1_SE in mouse models to assess muscle regeneration.
• Analysis of TEAD4-mediated chromatin looping and PI3K/AKT signaling pathway activation.
• Investigation of CircTPM1 interactions with MYH10 and MYL3.

Main Results:

• TPM1_SE deletion impaired myogenic differentiation and reduced TPM1 and CircTPM1 expression.
• Conditional TPM1_SE deletion led to reduced muscle mass and delayed regeneration.
• TPM1_SE drives TPM1 and CircTPM1 expression via TEAD4, coordinating cytoskeletal organization.
• CircTPM1 directly binds MYH10, promoting actomyosin assembly and myotube formation.
• TPM1_SE regulates the mechanosensitive NKX2.2-PI3K/AKT signaling pathway.

Conclusions:

• TPM1_SE is an evolutionarily conserved hub integrating epigenetic regulation and biomechanical processes in muscle regeneration.
• The findings highlight TPM1_SE's therapeutic potential for muscle regenerative medicine.
• The CircTPM1-mediated mechanism in cattle suggests TPM1_SE as a target for improving meat quality.