PTM encoding: decoding the mechanisms of exercise-induced metabolic memory through spatiotemporal modification networks

Post-translational modifications (PTMs) form a sophisticated regulatory layer that modulates cellular responses to physiological stimuli, notably exercise-triggered metabolic adaptations like skeletal muscle glucose uptake. Understanding PTM-mediated regulatory logic, namely how several well-characterized PTMs coordinate spatiotemporally to mediate distinct biological functions, has become a critical frontier in decoding metabolic memory mechanisms. Traditional paradigms focused on isolated signaling pathways struggle to account for the intricate network dynamics underlying these adaptations. This review synthesizes recent advances that clarify the role of PTM-mediated regulation in exercise-induced metabolic memory. We emphasize integrating cutting-edge technologies (single-cell multiomics, <i>in situ</i> mass spectrometry imaging). These tools enable constructing dynamic PTM profiles with exceptional spatial and temporal resolution. Innovations in fluorescence reporter probes additionally improve monitoring of PTM dynamics <i>in vivo</i>. We explore the molecular logic governing hierarchical PTM networks and interorgan communication, highlighting the central regulatory functions of AMPK/mTOR pathways. Additionally, we discuss emerging machine learning-based PTM clock models that provide quantitative frameworks to track metabolic states and advance precision exercise prescriptions. By bridging molecular insights with translational applications, this review offers a holistic view to advance our understanding of exercise-induced metabolic memory and facilitate developing personalized interventions. These conceptual and technological breakthroughs position PTM-mediated regulation as a transformative paradigm with notable academic value and clinical promise.