Branched‐Chain Amino Acids and Di‐Alanine Supplementation Attenuates Muscle Atrophy in a Murine Model of Cancer Cachexia

Aim: Cancer cachexia is a severe metabolic disorder leading to skeletal muscle atrophy. Muscle wasting is a major clinical problem in cachectic patients, as it limits the efficacy of chemotherapeutic treatments and worsens quality of life. Nutritional support based on branched-chain amino acids (BCAA) has been shown to be a promising approach to counteract cachexia-induced muscle atrophy, but its efficacy is still debated. Furthermore, the putative role of di-alanine (Di-Ala) supplementation has yet to be evaluated. The present study therefore sought to assess whether BCAA supplementation, alone or in combination with a Di-Ala peptide, could attenuate muscle wasting in a preclinical model of cancer cachexia. Methods: To this end, C26 tumor-bearing mice were administered BCAA supplementation, with or without Di-Ala. Body and muscle weights, as well as molecular, biochemical, and morphological analysis, were carried out to characterize prospective changes of markers involved in cachexia and muscle atrophy. Results: The main findings revealed that BCAA supplementation effectively prevented body weight loss and muscle atrophy. Of note, Di-Ala significantly amplified the effects of BCAA. These phenomena were found to be mediated by the suppression of pathways involved in protein catabolism. Conclusions: Collectively, these results highlight that innovative formulations containing Di-Ala, capable of increasing BCAA bioavailability, may be efficacious in counteracting muscle atrophy, especially during mild-to-moderate cancer cachexia.