Abstract
In this study, we investigated the effect of glutamine (Gln) supplementation on the signaling pathways regulating protein synthesis and protein degradation in the skeletal muscle of rats with streptozotocin (STZ)-induced diabetes. The expression levels of key regulatory proteins in the synthetic pathways (Akt, mTOR, GSK3 and 4E-BP1) and the degradation pathways (MuRF-1 and MAFbx) were determined using real-time PCR and Western blotting in four groups of male Wistar rats; 1) control, non-supplemented with glutamine; 2) control, supplemented with glutamine; 3) diabetic, non-supplemented with glutamine; and 4) diabetic, supplemented with glutamine. Diabetes was induced by the intravenous injection of 65 mg/kg bw STZ in citrate buffer (pH 4.2); the non-diabetic controls received only citrate buffer. After 48 hours, diabetes was confirmed in the STZ-treated animals by the determination of blood glucose levels above 200 mg/dL. Starting on that day, a solution of 1 g/kg bw Gln in phosphate buffered saline (PBS) was administered daily via gavage for 15 days to groups 2 and 4. Groups 1 and 3 received only PBS for the same duration. The rats were euthanized, and the soleus muscles were removed and homogenized in extraction buffer for the subsequent measurement of protein and mRNA levels. The results demonstrated a significant decrease in the muscle Gln content in the diabetic rats, and this level increased toward the control value in the diabetic rats receiving Gln. In addition, the diabetic rats exhibited a reduced mRNA expression of regulatory proteins in the protein synthesis pathway and increased expression of those associated with protein degradation. A reduction in the skeletal muscle mass in the diabetic rats was observed and was alleviated partially with Gln supplementation. The data suggest that glutamine supplementation is potentially useful for slowing the progression of muscle atrophy in patients with diabetes.
Highlights
The maintenance of normal skeletal muscle mass and size is required for locomotion, heat production and the control of intermediary metabolism [1] and is dependent upon many factors, including the functioning of efferent motor innervation [2] and an adequate supply of glucose, fatty acids, and trophic hormones [3]
Muscle wasting in diabetes is the result of damage to the intracellular signaling pathways that are involved in maintaining the balance between protein degradation and new protein synthesis [5], which depends on both the phosphorylation and de novo expression of specific regulatory proteins
Our study demonstrates a number of significant differences in glutamine regulation and in the protein-synthetic and proteindegradative pathways in the skeletal muscle of the STZ-diabetic rats compared with the non-diabetic rats
Summary
The maintenance of normal skeletal muscle mass and size is required for locomotion, heat production and the control of intermediary metabolism [1] and is dependent upon many factors, including the functioning of efferent motor innervation [2] and an adequate supply of glucose, fatty acids, and trophic hormones [3]. Muscle wasting in diabetes is the result of damage to the intracellular signaling pathways that are involved in maintaining the balance between protein degradation and new protein synthesis [5], which depends on both the phosphorylation and de novo expression of specific regulatory proteins. The skeletal muscle mass is controlled by the signaling pathways leading to protein synthesis, especially the IGF-1/PI3K/ Akt pathway and alternatively, pathways leading to degradation, such as MuRF-1- or MAFbx-dependent pathway intermediates [2,6]. Depending on the physiologic state of the muscle cell, Akt transduces signals that lead primarily to increased protein synthesis (by activating a number of specific downstream proteins, including mTOR, p70s6k, 4E-BP1 and GSK3) or to decreased degradation (using pathways dependent upon MuRF-1 and MAFbx). In the protein synthetic pathway, Akt activation leads to the formation of a signaling complex termed
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