Nutritional strategies against skeletal muscle wasting in cancer-associated cachexia: the role of β-hydroxybutyrate and polyunsaturated fatty acids

Cachexia is a multifactorial syndrome that occurs in many cancers, particularly in their advanced stages, decreasing the quality of life and lifespan of patients. One of the hallmarks of cancer-associated cachexia is skeletal muscle wasting. Multiple causes include inflammation, metabolic deregulation, energy utilization, endoplasmic reticulum and oxidative stress. Loss of skeletal muscle is characterised by an imbalance in protein homeostasis, with decreased anabolism (regulated by the Akt/GSK3/eIF2α and Akt/mTORC1 pathways) and increased catabolism (regulated by autophagy and the ubiquitin-proteasome system), as well as an impairment in myogenesis. Accumulating evidence suggests that dietary intervention of β-hydroxybutyrate, the major ketone body produced by ketogenesis, and n-3 polyunsaturated fatty acids may mitigate skeletal muscle wasting. Polyunsaturated fatty acids and β-hydroxybutyrate are able to favourably modulate inflammation, insulin resistance, unfolded protein response and stresses (such as metabolic stress and oxidative stress). A well-adapted nutritional strategy may include a "classic" diet supplemented with β-hydroxybutyrate and polyunsaturated fatty acids to maintain skeletal muscle integrity and reduce wasting.