# Regulatory roles of the circRNA–RBP axis in exercise-induced skeletal muscle remodeling: mechanistic controversies and translational illusions

## TL;DR

This paper discusses the role of circRNA-RBP interactions in muscle adaptation to exercise and highlights major issues in current research methods.

## Contribution

The paper introduces a new experimental framework to shift from speculative models to physiologically credible mechanisms in circRNA-RBP research.

## Key findings

- Current studies overestimate the ceRNA effects due to low endogenous circRNA levels.
- Evolutionary poor conservation of exercise-related circRNAs questions their functional relevance.
- The scaffolding model's specificity and technical limitations are major concerns.

## Abstract

Metabolic health and physical performance rely upon skeletal muscle adaptation that is a result of exercise. Recent advancements in high-throughput sequencing and functional genomics have successfully identified a vast landscape of exercise-responsive circRNAs, providing critical insights into the molecular complexity of muscle adaptation. While these studies have established a foundational framework for understanding the circRNA–RBP axis, there are serious issues related to current research. There are serious issues related to current research: an insufficient level of endogenous circRNA to produce substantial ceRNA effects, unconfirmed circRNA scaffolding due to overactivity of RBPs, poor conservation of so-called exercise-related circRNAs evolutionarily, and the over-interpretation of specific effects. The article focuses on basic concerns of the ceRNA model quantitative limitations, and specificity debate of the scaffolding model, current model and technical gaps, etc. and suggests an experimental framework transitioning from “narrative models” to “physiologically credible mechanisms,” offering references for future rigorous research and elucidating the authentic role of the circRNA–RBP axis.