Skeletal muscle metabolizes nutrients and supports physical activity by producing energy and synthesizing its constituent proteins. It also acts as a secretory organ that regulates systemic functions by secreting bioactive factors, referred to as myokines. Myokines can influence health through effects on gut functions and such as hormone secretion, immunity, and carcinogenesis risk, in association with physiological responses and benefits induced by exercise. On the other hand, the metabolic capacity of skeletal muscle is affected by various signals derived from the gut. The gut is responsible for digestion and absorption of nutrients and contributes to the supply of metabolic substrates. In addition, it acts as a barrier by preventing invasion of extrinsic factors such as bacteria, antigens, and endotoxins, thereby preventing excessive inflammatory responses and metabolic disturbances. It is also known that metabolites produced by gut bacteria regulate metabolism directly or indirectly. Therefore, healthy gut function is important for skeletal muscle metabolism, contributing to the prevention of metabolic diseases and frailty, and maintaining exercise performance. The science of the crosstalk between skeletal muscle and gut, i.e. the “Muscle-Gut Axis”, has led to novel perspectives of diet and exercise.