The role of secretion associate ras-related GTPase 1b in skeletal muscle insulin signaling

Abstract

Dysfunctional branched-chain amino acid (BCAA) catabolism increases intracellular branched-chain keto acids (BCKA), which inhibit insulin signaling. The discovery of Secretion Associated Ras-related GTPase-1B (Sar1b), a leucine sensor, raised the question if Sar1b alters BCAA flux in the muscle to influence insulin action, mitochondrial function, and protein synthesis. In my thesis, I examined if nutrient overload changes Sar1b content in the muscle, influencing intracellular BCKA levels, and thereby perturbing insulin signaling, substrate metabolism, and mitochondrial function. Increased circulating BCKAs in diet-induced obese mice were associated with decreased Sar1b protein content in the gastrocnemius muscle. In C2C12 cells, Sar1b knockdown increased intracellular BCKA content, reduced pyruvate-linked mitochondrial respiration with a concomitant decline of insulin-stimulated phosphorylation of protein kinase B, glycogen synthase kinase, ribosomal S6, p70S6K, mTOR, and extracellular receptor kinase. Increased understanding of Sar1b and its skeletal muscle interacting partners will uncover novel therapeutic targets to maintain insulin homeostasis during obesity.