1. 4-PBA prevents diabetic muscle atrophy in rats by modulating ER stress response and ubiquitin-proteasome system.
- Author
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Reddy SS, Shruthi K, Joy D, and Reddy GB
- Subjects
- Animals, Apoptosis drug effects, Biomarkers metabolism, Diabetes Mellitus, Experimental chemically induced, Diabetes Mellitus, Experimental pathology, Injections, Intraperitoneal, Male, Muscular Atrophy chemically induced, Muscular Atrophy pathology, Phenylbutyrates administration & dosage, Rats, Rats, Sprague-Dawley, Streptozocin, Diabetes Mellitus, Experimental prevention & control, Endoplasmic Reticulum Stress drug effects, Muscular Atrophy prevention & control, Phenylbutyrates pharmacology, Proteasome Endopeptidase Complex metabolism, Ubiquitin metabolism
- Abstract
Purpose: Skeletal muscle is severely affected in diabetes leading to muscle atrophy. Previously we reported the role of ER stress in muscle atrophy due to hyperglycemia. Hence, in the present study, we investigated the effect of a classical ER stress inhibitor, 4-phenylbutyric acid (PBA), on muscle atrophy in diabetic rats., Methods: Diabetes was induced in male rats by streptozotocin, and PBA was administered (40 mg/kg/day; intraperitoneal) after two months of diabetes for two more months. Gastrocnemius muscle is collected after four months of experimental period. The cross-sectional area of myocytes was measured on Hematoxylin and Eosin stained muscle sections. Protein levels of ER stress markers, ubiquitin-proteasome system (UPS) components, and apoptosis were analysed by immunoblot. Proteasomal activity and apoptotic cells were measured., Results: ER stress markers (GRP78, ATF6, ATF4 and CHOP) that are elevated in diabetes are decreased with PBA treatment. PBA also averted diabetes-induced alterations in UPS (higher levels of E1, atrogin-1, UCHL1 and UCHL5, accumulation of ubiquitinated proteins and increased proteasomal activity). Apoptosis mediators-p53, BAX, and cleaved caspase-3 protein levels, and TUNEL positive cells were decreased in PBA treated diabetic rats. PBA notably improved the muscle-cross sectional area., Conclusions: Results highlighted the therapeutic potential of PBA in diabetes muscle wastage., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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