Amino Acids as Metabokines in Hypercatabolic States: Rethinking Nutritional Protein-Based Strategies Beyond Caloric Support

The clinical management of nutrition in acute and chronic diseases requires an integrated understanding of the interactions between energy intake, dietary protein, and amino acids (AAs). Many conditions (including sepsis, major trauma, cancer cachexia, chronic heart failure, chronic obstructive pulmonary disease, renal and liver failure, autoimmune diseases, and aging) share a common pathophysiological feature: the hypercatabolic state (HCS). HCS is characterized by systemic inflammation and neuroendocrine activation that increase basal metabolic rate, induce insulin resistance, and accelerate skeletal muscle proteolysis, leading to negative nitrogen balance, sarcopenia, and cachexia. Under these conditions, skeletal muscle acts as a metabolic reservoir of AAs mobilized to support energy production, gluconeogenesis, immune function, and vital organ metabolism, often at the expense of lean body mass and clinical outcomes. This narrative review examines the distinct and non-overlapping roles of calories, proteins, and AAs in metabolic regulation, with a particular focus on HCS. Calories primarily act as a permissive factor for protein utilization, whereas proteins and especially essential amino acids (EAAs) function not only as substrates for protein synthesis but also as signaling molecules (metabokines) regulating anabolic and catabolic pathways, including mTORC1 and AMPK. Energy provision alone is insufficient to prevent muscle loss when EAA availability is inadequate, while high protein intake without sufficient energy fails to sustain anabolism due to anabolic resistance. Evidence indicates that protein quality and the balanced availability of all EAAs are more critical for lean mass preservation than total caloric intake alone. Strategies based solely on calorie provision or protein quantity are therefore limited, whereas targeted EAA supplementation may partially overcome anabolic resistance in selected hypercatabolic conditions. Overall, this review supports a shift from calorie-centered nutrition toward a signal-based, quality-oriented approach, based on personalized needs, that integrates metabolic status, protein quality, and AA signaling to preserve lean body mass and improve clinical outcomes.