The observed elevation in TRAP1 protein abundance requires further validation

to determine whether enhanced TRAP content may limit cell damage and regulate cell repair for restoration or apoptosis after elevated stress response [60]. The functional role of PARK7 in skeletal muscle is still unknown, but PARK7 knockout mice show a reduced mitochondrial ACO2 activity and enhanced mitochondrial glutathione peroxidase activity, which suggests a deficient mitochondrial H2O2 scavenging function [61] and [62]. We report that ACO2 abundance is increased in myotubes from T2D patients, while PARK7 protein level is reduced. Whether PS-341 mouse there is a direct connection between these proteins in metabolic pathways and disease predisposition requires further investigation. However, differential protein profiles of chaperones in myotubes derived from T2D patients supports the the growing idea that disturbances in the protein maintanance system may cause impaired mitochondrial quality control system and thereafter a fundamental disturbance of cellular

metabolic activity [55]. A comparison of the proteome of myotubes derived from NGT versus T2D patients revealed that several proteins involved in mRNA processing, regulation and transcription are altered. This finding advocates the idea that T2D imparts a disease-related inhibition of basic cellular functions in skeletal muscle. For example, KHSRP, a key mediator of mRNA decay known to promote the biogenesis of a subset of microRNAs [63], was more abundant Cyclin-dependent kinase 3 in myotubes from E7080 research buy T2D patients. KHSRP is phosphorylated by p38MAPK and Akt in the regulation of the mRNA degradation pathway [64] and turnover of myogenic mRNA [65]. Therefore, while KHSRP is more abundant in T2D myotubes, its role and function requires further study in relation to insulin

resistance. Proteome analysis also revealed that myotubes derived from T2D patients possess higher levels of the DNA repair proteins, XRCC5, and RECQL. The function of these proteins in metabolism and T2D is still elusive. Whether an increased DNA repair activity may reflect an enhanced oxidative stress caused by increased ROS and/or reduced oxidative defense remains to be determined. The differential proteome signatures of myotubes derived from people with T2D versus NGT offers new insights into causes of T2D, highlighting pathways involving disturbances in energy metabolism, oxidative stress response, protein dynamics and gene regulation. The analysis presented here demonstrates a clear disturbance of the protein signature in skeletal muscle myotubes derived from T2D patients compared to NGT subjects. Our results reveal that metabolic impairments, reductions in GSH concentration, and differences in the protein profile are retained in cultured differentiated myotubes from T2D subjects. Thus, our findings emphasize that an intrinsic proteome exists, directed by either epigenetic or genetic factors, in skeletal muscle from T2D patients.