Kinase-phosphatase balance in exercise adaptation: phosphorylation programs, PTM crosstalk, and actionable gaps

Phosphorylation is set by the opposing activities of kinases and phosphatases and this regulation likely contributes to exercise-induced adaptation. It does so by regulating mitochondrial biogenesis, muscle remodeling, and metabolic flexibility. The process by which exercise activates the AMPK, MAPK, and Akt-mTOR pathways, and how phosphatases (MKP, PHLPP, and PHPT1/LHPP) limit signal amplitude and duration to avoid maladaptive behavior, has been extensively studied. Some data suggest PHLPP2 may increase after HIIT, which could contribute to limiting Akt activity. In contrast, endurance training has been associated in some studies with relatively lower PHLPP activity; this observation may be consistent with sustained Akt-dependent mitochondrial adaptations, but direct causal evidence is limited. Systems-level phosphoproteomics unveils tissue- and time-resolved, modality-dependent phosphorylation programs and situates this axis within broader PTM crosstalk (lactylation). We outline manageable gaps linking kinase-phosphatase interactions to chromatin regulation, delineate non-canonical histidine phosphorylation, and present a condensed roadmap (time-resolving, compartment-aware phosphoproteomics integrated with epigenomic profiling) that connects enzyme function to phenotype and provides precise exercise recommendations and metabolic disease therapies.