The Effects and Mechanisms of Exercise on The Crosstalk Among Post-translational Modifications of Proteins

Post-translational modification (PTM) of proteins refers to the covalent addition of functional groups to amino acid residues or structural alterations in proteins during or after translation, primarily mediated by enzymatic reactions and secondarily by non-enzymatic chemical processes. PTM crosstalk denotes interactions between distinct modification sites or different types of modifications on a single protein, which regulate protein functions through synergistic, antagonistic, or cascading mechanisms. Lactylation, phosphorylation, and acetylation are three pivotal types of protein PTMs, involving the covalent attachment of lactic acid, phosphate, and acetyl groups to specific amino acid residues, respectively. These reversible modifications are dynamically regulated by cellular metabolic status and signaling pathways. Phosphorylation primarily facilitates rapid signal transduction; acetylation broadly regulates metabolism and gene expression; and lactylation is closely associated with high-lactate microenvironments and metabolic stress. Through competitive binding at identical or adjacent sites, reciprocal modulation of metabolite levels, and cross-regulation of signaling pathways, these three modifications form an intricate crosstalk network that coordinately regulates cellular adaptive responses to internal and external environmental changes. As a physiological stimulus with broad effects on bodily functions, exercise induces a series of changes in intracellular metabolism and signal transduction, thereby influencing PTMs and their crosstalk. On one hand, exercise activates multiple interconnected cellular systems, including energy metabolism, signal transduction, and molecular interaction networks. Within the energy metabolism system, exercise alters the pattern of cellular ATP production and utilizes metabolic intermediates as signaling molecules to directly or indirectly modulate the activity of enzymes involved in these three modifications. In the signal transduction system, exercise activates pathways such as AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase (MAPK), which precisely regulate the activity and subcellular localization of modification-related enzymes <italic>via</italic> phosphorylation cascades. In the molecular interaction system, exercise promotes protein-protein and protein-metabolite interactions, thereby remodeling the regulatory network of PTMs. On the other hand, exercise facilitates crosstalk among lactylation, phosphorylation, and acetylation through a multi-level progressive regulatory model: “metabolic initiation → signal transduction → molecular interaction”. At the metabolic level, alterations in metabolites provide the initial driving force for crosstalk; signaling pathways amplify these signals and precisely modulate the direction of crosstalk through cascade reactions; and molecular interactions further integrate signals to establish a refined regulatory network. Ultimately, this multi-system and multi-level crosstalk enables precise regulation of cell proliferation, differentiation, and apoptosis, thereby mediating cellular adaptation to exercise and playing a central role in enhancing exercise capacity and improving metabolic health. This article systematically examines how exercise influences crosstalk among these three key PTMs—lactylation, phosphorylation, and acetylation—and the underlying mechanisms, including the regulation of metabolite levels, modification-related enzyme activity, cellular signaling pathways, metabolic homeostasis, and gene expression. This work provides a novel perspective for gaining deeper insights into how exercise regulates physiological functions.