Ablation of LAT2 Transporter Causes Intramuscular Glutamine Accumulation and Inhibition of Fasting-Induced Proteolysis

Abstract

Background: The neutral amino acid transporter SLC7A8 (LAT2) has been described as a key regulator of metabolic adaptation.LAT2 mutations in human populations have been linked to the early onset of age-related hearing loss and cataract growth. AsLAT2 was previously found to be highly expressed in skeletal muscle, here we characterised its role in the regulation of skeletalmuscle amino acid flux and metabolic adaptation to fasting.Methods: Wild-type (WT) and LAT2 knock-out (LAT2KO) mice were exposed to short- and long-periods of fasting (16 and48 h). The impact of the absence of LAT2 on amino acid content, gene expression, proteolysis activity, muscle tone, and histol-ogy was measured. To characterise the impact on muscle degradation, we tested LAT2 KO mice in cancer-associated cachexia,streptozocin-induced Type-1 diabetes, and ageing models.Results: LAT2KO mice experienced a notable reduction in body weight during fasting (WT:14% and LAT2KO:18%, p = 0.02), witha greater reduction in fat mass (0.5-fold, p = 0.013) and a higher relative retention of muscle mass (1.3-fold, p = 0.0003) comparedwith WT. The absence of LAT2 led to increased intramuscular glutamine (Gln) accumulation (6.3-fold, p < 0.0001), accompanied