Exercise as A Biological Driver of Skeletal Muscle Regeneration and Repair: Implications for Regenerative Rehabilitation.

Abstract

The Joel A. DeLisa Lecture on regenerative rehabilitation was presented by Dr. Thomas Rando on February 27, 2025, at the Association of Academic Physiatrists Annual Scientific Meeting. This article follows the key themes presented in that lecture, exploring the regenerative potential of exercise as a biophysical stimulus and focusing on its ability to modulate muscle stem cell (MuSC) function and enhance tissue repair following muscle injury. In aged mice, exercise restores youthful properties to MuSCs, thereby enhancing regenerative capacity that declines with age. In models of volumetric muscle loss (VML), exercise improves the engraftment and integration of transplanted MuSCs by promoting myogenesis, angiogenesis, and reinnervation. Additionally, exercise shifts systemic and local immune responses toward a pro-regenerative state, enhancing stem cell function across multiple tissues. Exercise acts as a potent, non-invasive regenerative intervention with direct effects on stem cell biology and tissue repair. These findings highlight the potential for integrating exercise-based rehabilitation with emerging biologic therapies in clinical practice, offering new strategies for improving recovery after injury. In this context, physiatrists and physical therapists will play a central role in the emerging field of regenerative rehabilitation.