Two-Way Communication Between Skeletal Muscle and Myokines

Myokines are defined as a class of bioactive molecules-including metabolites, peptides, and proteins-released from skeletal muscle cells and promoted by exercise. Recently, myokine-mediated muscle-organ crosstalk has sparked increased interest. Skeletal muscle secretes hundreds of myokines in an autocrine, paracrine, or endocrine manner, mediating the crosstalk between skeletal muscle and skeletal muscle itself, bone, fat, liver, and so on to regulate the physiological state of multiple organs, exerting a wide range of benefits of exercise. The relationship between muscle and myokines may be better understood as an exercise-responsive regulatory framework involving skeletal muscle and myokines, although direct evidence for an integrated bidirectional feedback network remains incomplete. In the network, myokines regulate skeletal muscle metabolism and remodeling through autocrine/paracrine actions, while exercise-induced muscle-derived signals may also contribute to long-lasting systemic adaptations involving immune mobilization, redox homeostasis, gut microbiota-related metabolic remodeling, and gut-muscle-bone crosstalk. Therefore, the distinct feature of skeletal muscle is not the mere presence of bidirectional signaling but its large mass, fiber-type metabolic heterogeneity, and direct responsiveness to repeated mechanical stimuli during exercise. On the one hand, as a source of myokines, the stimulation of skeletal muscle affects the production of myokines through various signaling pathways. On the other hand, myokines affect skeletal muscle function, such as glucose absorption, fatty acid oxidation, skeletal muscle mass, and muscle fiber type transformation. What's more, some myokines are muscle fiber type-specific, meaning that the expression of myokines may be influenced by muscle fiber type. Based on these, this review aims to summarize current evidence for exercise-responsive interactions between skeletal muscle and myokines and to identify where feedback regulation remains hypothetical.