Study of the tRNA-derived fragment expression profile in rat pancreatic islets of diabetes-susceptible low-protein (LP) exposed rats
In this study, we discovered cytosolic and mitochondrial fragments resulting from tRNA and mt-tRNA cleavage, which may act as new regulators of cellular and metabolic functions. The so-called LP rat model consists of 22-day-old rats whose mothers have been subjected to a low protein diet during gestation and lactation. These offspring have impaired pancreatic development with reduced ß-cell mass, glucose-stimulated insulin secretion defect and are more prone to develop diabetes in adulthood. We identified hundreds of these fragments as being changed in the pancreatic islets of LP rats and compared them to chow diet (CD) exposed rats.  In our analysis, we identified 6164 tRFs in the islets of LP rats, among which 256 exhibited significant changes (= 2 fold; adjusted p value = 0.05) compared to controls. Of these, 113 tRFs showed increased levels, while 143 tRFs showed decreased levels in the LP rats. We focused our investigations on mitochondrial tRFs (mt-tRFs) that show significant alterations in both, adult pre-diabetic mice (db/db) and LP rats. We selected the mt-tRF-LeuTAA fragment  for further investigation, as its level is reduced in the islets of db/db mice and LP rats, while being abundant in ß-cells. mt-tRF-LeuTAA fragment is derived from the cleavage of tRNA-LeuTAA encoded by the mitochondrial genome. We demonstrated that mt-tRF-LeuTAA acts as a key regulator of mitochondrial OXPHOS functions, mitochondrial membrane potential, the insulin secretory capacity of ß-cells, and the insulin sensitivity of myotube muscle cells. Overall design: In order to characterize the expression profile of tRFs (tRNA-derived fragments) under conditions that promote diabetes development, we isolated total RNA from pancreatic islets of four low-protein (LP) exposed rats and compared it to that of five chow diet (CD) exposed rats.