Branched-chain amino acid supplementation: impact on signaling and relevance to critical illness

Abstract

The changes that occur in mammalian systems following trauma and sepsis, termed systemic inflammatory response syndrome, elicit major changes in carbohydrate, protein, and energy metabolism. When these events persist for too long they result in a severe depletion of lean body mass, multiple organ dysfunction, and eventually death. Nutritional supplementation has been investigated to offset the severe loss of protein, and recent evidence suggests that diets enriched in branched-chain amino acids (BCAAs) may be especially beneficial. BCAAs are metabolized in two major steps that are differentially expressed in muscle and liver. In muscle, BCAAs are reversibly transaminated to the corresponding α-keto acids. For the complete degradation of BCAAs, the α-keto acids must travel to the liver to undergo oxidation. The liver, in contrast to muscle, does not significantly express the branched-chain aminotransferase. Thus, BCAA degradation is under the joint control of both liver and muscle. Recent evidence suggests that in liver, BCAAs may perform signaling functions, more specifically via activation of mTOR (mammalian target of rapamycin) signaling pathway, influencing a wide variety of metabolic and synthetic functions, including protein translation, insulin signaling, and oxidative stress following severe injury and infection. However, understanding of the system-wide effects of BCAAs that integrate both metabolic and signaling aspects is currently lacking. Further investigation in this respect will help rationalize the design and optimization of nutritional supplements containing BCAAs for critically ill patients.

Figure 1

BCAA metabolism in liver and muscle. BCAAs absorbed from the gut reach the liver where they are taken up and play various signaling and protein synthetic roles. The BCAA catabolic pathway takes place within mitochondria, and consists of two major steps: reversible transamination with alpha-ketoglutarate to form BCKAs, followed by irreversible decarboxylation to form CoA compounds which enter the TCA cycle. The transamination step catalyzed by branched chain aminotransferase (BCAT) mostly occurs in muscle because this is where BCAT expression is highest. On the other hand, BCKA decarboxylation, catalyzed by branched chain ketoacid dehydrogenase (BCKDH), as well as later steps leading to complete oxidation, occur mainly in liver (19).