Three-dimensional network of creatine metabolism: From intracellular energy shuttle to systemic metabolic regulatory switch

BACKGROUND: Creatine serves as an intracellular shuttle for high-energy phosphate bonds, enabling rapid ATP transfer from energy-producing to energy-consuming cellular compartments. In skeletal muscle, creatine coordinates energy distribution among mitochondrial oxidative phosphorylation, glycolysis, and the phosphagen system. Consequently, creatine supplementation acutely enhances muscular performance and is widely utilized as an ergogenic aid in power-based sports. Recent studies demonstrate that enhanced creatine metabolism in adipose tissue promotes brown adipocyte renewal and boosts energy expenditure in cold environments or sedentary conditions, thereby improving overall systemic metabolism. Beyond its traditional role as an exercise supplement, the creatine metabolic network has emerged as a promising therapeutic target for metabolic disorders. SCOPE OF REVIEW: This review begins by revisiting the history and latest advancements in creatine research, and ultimately proposes three dimensions for the current explanation of creatine metabolism: (1) subcellular energy transport; (2) muscle-fat metabolic axis; (3) systemic energy sensing and metabolic reprogramming. MAJOR CONCLUSIONS: The creatine cycle enables directed energy flow through mitochondrial supercomplexes (VDAC/ANT-CK) and resets systemic metabolism via subcellular energy tunnels and inter-organ interactions. Creatine kinase (CK) condensates, through liquid-liquid phase separation, can rapidly meet energy demands during exercise. Therefore, targeting the dynamics of the CK phase may be promising for enhancing athletic performance and improving metabolic diseases.