Repository of Research and Investigative Information

Repository of Research and Investigative Information

Ilam University of Medical Sciences

Protein tyrosine phosphatase 1B inhibition ameliorates palmitate-induced mitochondrial dysfunction and apoptosis in skeletal muscle cells

Sun Aug 14 02:56:03 2022

(2013) Protein tyrosine phosphatase 1B inhibition ameliorates palmitate-induced mitochondrial dysfunction and apoptosis in skeletal muscle cells. Free Radical Biology and Medicine. pp. 1435-1446. ISSN 0891-5849

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Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin signaling pathway and is considered a promising therapeutic target in the treatment of diabetes. However, the role of PTP1B in palmitate-induced mitochondrial dysfunction and apoptosis in skeletal muscle cells has not been studied. Here we investigate the effects of PTP1B modulation on mitochondrial function and apoptosis and elucidate the underlying mechanisms in skeletal muscle cells. PTP1B inhibition significantly reduced palmitate-induced mitochondria] dysfunction and apoptosis in C2C12 cells, as these cells had increased expression levels of PGC-1 alpha, Tfam, and NRF-1; enhanced ATP level and cellular viability; decreased TUNEL-positive cells; and decreased caspase-3 and -9 activity. Alternatively, overexpression of PTP1B resulted in mitochondrial dysfunction and apoptosis in these cells. PTP1B silencing improved mitochondrial dysfunction by an increase in the expression of SIRT1 and a reduction in the phosphorylation of p65 NF-kappa B. The protection from palmitate-induced apoptosis by PTP1B inhibition was also accompanied by a decrease in protein level of serine palmitoyl transferase, thus resulting in lower ceramide content in muscle cells. Exogenous addition of C2-ceramide to PTP1B-knockdown cells led to a reduced generation of reactive oxygen species (ROS), whereas PTP1B overexpression demonstrated an elevated ROS production in myotubes. In addition, PTP1B inhibition was accompanied by decreased JNK phosphorylation and increased insulin-stimulated Akt (Ser473) phosphorylation, whereas overexpression of PTP1B had the opposite effect. The overexpression of PTP1B also induced the nuclear localization of FOXO-1, but in contrast, suppression of PTP1B reduced palmitate-induced nuclear localization of FOXO-1. In summary, our results indicate that PTP1B modulation results in (1) alterations in mitochondrial function by changes in the activity of SIRTI/NF-kappa B/PGC-1 alpha pathways and (2) changes in apoptosis that result from either a direct effect of PTP1B on the insulin signaling pathway or an indirect influence on ceramide content, ROS generation, JNK activation, and FOXO-1 nuclear translocation. (C) 2013 Elsevier Inc. All rights reserved.

Item Type: Article
Creators:
CreatorsEmail
Taheripak, G.UNSPECIFIED
Bakhtiyari, S.UNSPECIFIED
Rajabibazl, M.UNSPECIFIED
Pasalar, P.UNSPECIFIED
Meshkani, R.UNSPECIFIED
Keywords: Palmitate PTP1B Apoptosis Mitochondrial dysfunction Free radicals endoplasmic-reticulum stress factor-kappa-b fatty-acid oxidation insulin sensitivity c2c12 myotubes human obesity down-regulation beta-cells expression ptp1b Biochemistry & Molecular Biology Endocrinology & Metabolism
Divisions:
Page Range: pp. 1435-1446
Journal or Publication Title: Free Radical Biology and Medicine
Journal Index: ISI
Volume: 65
Identification Number: https://doi.org/10.1016/j.freeradbiomed.2013.09.019
ISSN: 0891-5849
Depositing User: مهندس مهدی شریفی
URI: http://eprints.medilam.ac.ir/id/eprint/693

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