Ketone bodies (i.e., acetoacetate (AcAc), beta-hydroxybutyrate (BHB), and acetone) are lipid-derived metabolites produced primarily in hepatic mitochondria. Endogenous ketone body production is markedly amplified during periods of low carbohydrate availability, such as prolonged fasting, starvation, or adherence to a ketogenic diet, where they serve as an alternative oxidative fuel for extrahepatic tissues, including the brain, heart, and skeletal muscle. Beyond their role in energy metabolism, ketone bodies are now increasingly recognized as signaling molecules capable of regulating diverse cellular processes, prompting growing interest in their therapeutic potential across a range of physiological and clinical contexts.

Recently, orally ingested exogenous’ ketone supplements have become available that can rapidly induce a transient increase in blood ketone body concentration, referred to as ‘acute nutritional ketosis’. Exogenous ketone supplements permit direct testing of the metabolic effects of elevated blood ketone body concentration without the confounding influence of widespread physiological changes associated with fasting, starvation, or ketogenic diets. The availability of exogenous ketone supplements has contributed to increased interest in the prospective therapeutic applications of ketone bodies. An emerging area of interest is the role of ketone bodies in the regulation of skeletal muscle protein metabolism. Historically, ketone bodies were proposed to spare body protein during prolonged fasting by reducing the reliance on amino acids for gluconeogenesis as the brain transitions to ketone bodies as a primary fuel source. This longstanding hypothesis has stimulated renewed investigation into the role of ketone bodies in the regulation of skeletal muscle protein turnover.

This presentation will examine current evidence demonstrating that ketone bodies influence both muscle protein synthesis and muscle protein breakdown. Acute studies in healthy adults indicate that exogenous ketone supplementation can augment postprandial muscle protein synthesis, while experimental models of inflammatory stress suggest ketone bodies may suppress muscle protein breakdown, resulting in a more favorable net protein balance. The mechanisms underlying these effects remain incompletely understood but are thought to involve actions beyond their role as a metabolic fuel, including modulation of intracellular signaling pathways regulating protein turnover, attenuation of inflammatory signaling, and changes in cellular energetics.

This presentation will critically evaluate the mechanistic and translational evidence supporting ketone bodies as regulators of skeletal muscle protein metabolism. Although the current literature suggests ketone bodies may promote an anabolic environment and contribute to the preservation of skeletal muscle under certain catabolic conditions, many questions remain regarding the underlying mechanisms, the influence of age and disease, and the long-term effects of exogenous ketone supplementation on muscle mass and function. By integrating recent advances in ketone body biology with emerging evidence on skeletal muscle protein metabolism, this presentation will examine the role of ketone bodies in the regulation of muscle protein turnover and discuss their potential as a nutritional strategy to support skeletal muscle health in aging and disease.