# The Evolutionarily Conserved TPM1 Super‐Enhancer Drives Skeletal Muscle Regeneration via Mechanotransduction Signaling

## TL;DR

A conserved genetic region called TPM1 super-enhancer helps muscles regenerate by linking epigenetic control with mechanical signals in cells.

## Contribution

The study reveals a conserved super-enhancer that connects epigenetics and biomechanics during muscle regeneration.

## Key findings

- TPM1 super-enhancer deletion impairs myogenic differentiation and reduces TPM1 and CircTPM1 expression.
- TPM1 super-enhancer regulates muscle regeneration via TEAD4-mediated chromatin looping and PI3K/AKT signaling.
- CircTPM1 enhances actomyosin assembly through MYH10 and MYL3, aiding myotube formation and muscle regeneration.

## Abstract

Super‐enhancers (SEs) are critical epigenetic regulators of tissue regeneration, yet their interplay with cellular biomechanics during myogenic differentiation remains unexplored. Here, the TPM1 locus, encoding a core actin‐stabilizing protein essential for skeletal muscle regeneration, harbors an evolutionarily conserved SE (TPM1_SE) that may bridge epigenetic control and mechanotransduction. In vitro, TPM1_SE deletion impaired myogenic differentiation and diminished expression of both TPM1 and its circular RNA (circRNA) isoform, CircTPM1. Conditional deletion of TPM1_SE significantly reduce muscle mass and delayed regenerative progression. Mechanistically, TPM1_SE drives expression of linear TPM1 mRNA (mice) and CircTPM1 (bovine) via TEAD4‐mediated chromatin looping, coordinating cytoskeletal reorganization during myotube formation. These effects are mediated via activation of the canonical PI3K/AKT signaling pathway through interaction with NKX2.2—a pathway mechanosensitive to cellular tension. Loss of TPM1_SE disrupted NKX2.2‐PI3K/AKT signaling. Crucially, CircTPM1 directly bound MYH10, enhancing MYL3‐dependent actomyosin assembly, which potentiates cytoskeletal reorganization during myotube formation. Collectively, this findings establish TPM1_SE as an evolutionarily conserved hub integrating epigenetic regulation and biomechanical output. While the murine model underscores its therapeutic potential in muscle regenerative medicine, the bovine CircTPM1‐mediated mechanism highlights TPM1_SE as a promising target for genetic improvement of meat quality in livestock.

By integrating biomechanical and epigenetic cues, the evolutionarily conserved TPM1 super‐enhancer drives myogenesis via TEAD4‐mediated chromatin looping. This mechanism produces species‐specific outputs (linear TPM1 mRNA in mice and CircTPM1 in bovine) that activate PI3K/AKT mechanotransduction and the MYH10/MYL3 axis to execute cytoskeletal remodeling, myotube formation, and ultimately, enhanced muscle regeneration.