The Unified CAPN3 Model — Integrating Molecular, Mechanical, and Regenerative Dynamics in Calpainopathy and the Therapeutic Rationale for AAV-CAPN3 Gene Restoration

This preprint proposes a unified signaling-based pathomechanistic model of Calpainopathy (LGMDR1), integrating CAPN3’s structural, calcium-regulatory, and RTK–RAS–MAPK stabilization functions. The work presents a mechanistic explanation for exercise sensitivity, delayed recovery, impaired regeneration, and long-term satellite-cell decline. A rationale is provided for AAV-CAPN3 gene restoration, along with a 6–12–24 month predictive model and a proposed exercise-based therapeutic synergy framework. The aim is to support collaboration among muscle biologists, RTK/MAPK experts, calcium signaling researchers, regeneration specialists, and gene-therapy developers.