Implication of altered ubiquitin-proteasome system and ER stress in the muscle atrophy of diabetic rats

• Published in: Archives of biochemistry and biophysics 2018-02, Vol.639, p.16-25
• Main Authors: Reddy, S. Sreenivasa, Shruthi, Karnam, Prabhakar, Y. Konda, Sailaja, Gummadi, Reddy, G. Bhanuprakash
• Format: Article
• Language: English
• Subjects: Animals; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Endoplasmic Reticulum Stress; ERAD; Leupeptins - pharmacology; Male; MG132; Muscle Proteins - metabolism; Muscle wasting; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy - chemically induced; Muscular Atrophy - drug therapy; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Proteasome Endopeptidase Complex - metabolism; Proteasome inhibitor; Proteasome Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Tripartite Motif Proteins - metabolism; Type 1 diabetes; Ubiquitin - metabolism; Ubiquitin Thiolesterase - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitinated Proteins - metabolism; Vesicular Transport Proteins - metabolism
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2017.12.015

Skeletal muscle is adversely affected in type-1 diabetes, and excessively stimulated ubiquitin-proteasome system (UPS) was found to be a leading cause of muscle wasting or atrophy. The role of endoplasmic reticulum (ER) stress in muscle atrophy of type-1 diabetes is not known. Hence, we investigated the role of UPS and ER stress in the muscle atrophy of chronic diabetes rat model. Diabetes was induced with streptozotocin (STZ) in male Sprague-Dawley rats and were sacrificed 2- and 4-months thereafter to collect gastrocnemius muscle. In another experiment, 2-months post-STZ-injection diabetic rats were treated with MG132, a proteasome inhibitor, for the next 2-months and gastrocnemius muscle was collected. The muscle fiber cross-sectional area was diminished in diabetic rats. The expression of UPS components: E1, MURF1, TRIM72, UCHL1, UCHL5, ubiquitinated proteins, and proteasome activity were elevated in the diabetic rats indicating activated UPS. Altered expression of ER-associated degradation (ERAD) components and increased ER stress markers were detected in 4-months diabetic rats. Proteasome inhibition by MG132 alleviated alterations in the UPS and ER stress in diabetic rat muscle. Increased UPS activity and ER stress were implicated in the muscle atrophy of diabetic rats and proteasome inhibition exhibited beneficiary outcome.