Chemical modification of muscle protein in diabetes

Alt, Nadja; Carson, James A.; Alderson, Nathan L.; Wang, Yuping; Nagai, Ryoji; Henle, Thomas; Thorpe, Suzanne R.; Baynes, John W.

doi:10.1016/j.abb.2004.03.012

Cited by 59 publications

(53 citation statements)

References 19 publications

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“…Their results indicated that both myosin structure and actin-myosin motility could be altered by exposing myosin to glucose. Alt et al [12] showed accumulation of AGEs, including N -(carboxymethyl)-lysine (CML), in both myofibrillar protein and total muscle protein fractions of gastrocnemius muscle in diabetic rats. This in vivo study of muscle suggests that specific muscle proteins are targets for glycation.…”

Section: Introductionmentioning

confidence: 99%

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Advanced Glycation End Product in Diabetic Rat Skeletal Muscle in vivo

et al. 2006

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Background: Advanced glycation end products (AGEs) are implicated in the etiology of diabetic complications in the kidney, nerve and eye. Skeletal muscle contractile parameters have also been found to be altered in diabetes. Glycation has not been extensively studied in skeletal muscle, but AGE-modified proteins may influence contractility. Objective and Methods: The aim of this study was to use immunohistochemistry to identify distribution patterns of the AGE NΕ-(carboxymethyl)-lysine in plantaris muscle of diabetic rats. Results: Results revealed the presence of NΕ-(carboxymethyl)-lysine intracellularly and also at sites along the myofiber periphery. The number of myofibers immunolabeling for AGE in animals with diabetes was more than 4-fold greater than in control animals. Additionally, there was a greater proportion of slow + fast myosin heavy chain coexpression in the AGE-positive cells from diabetic animals than in AGE-positive fibers from control animals. No significant difference was present between cross-sectional areas of AGE-positive fibers and AGE-negative fibers within the respective experimental groups. Conclusions: AGE accumulation is greater in skeletal muscle in vivo from diabetic animals than in control animals. This AGE accumulation appears to be associated with fiber-type transformation rather than with myofiber size. Further study is needed to determine the identity of these AGE-modified proteins and to determine how they influence skeletal muscle function in diabetes.

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Section: Introductionmentioning

confidence: 99%

“…In contrast to the quantification of AGEs with chromatography and mass spectrometry [12] , immunohistochemistry provides a unique perspective on AGE accumulation. With immunohistochemistry, it is possible to evaluate an entire muscle cross-section to determine the number of AGE-positive fibers and to survey their distribution pattern.…”

Section: Introductionmentioning

confidence: 99%

Advanced Glycation End Product in Diabetic Rat Skeletal Muscle in vivo

et al. 2006

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“…The accumulation of sugar and lipid-derived chemical modifications on proteins is associated with the etiology of several age-related diseases, including diabetes and its complications (1,2). The irreversible adducts formed, termed advanced glycation/lipoxidation end products (AGE/ALEs), 2 accumulate over time on long lived proteins, such as collagens, affecting the solubility, elasticity, and proteolytic digestibility of the protein (3).…”

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confidence: 99%

“…The irreversible adducts formed, termed advanced glycation/lipoxidation end products (AGE/ALEs), 2 accumulate over time on long lived proteins, such as collagens, affecting the solubility, elasticity, and proteolytic digestibility of the protein (3). AGE/ALEs are considered important mediators of the pathogenesis of diabetic complications through engagement of scavenger receptors, such as RAGE (receptor for AGE) and activation of proinflammatory signaling pathways (4).…”

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confidence: 99%

“…AGE/ALEs are considered important mediators of the pathogenesis of diabetic complications through engagement of scavenger receptors, such as RAGE (receptor for AGE) and activation of proinflammatory signaling pathways (4). To date, the study of AGE/ALEs has focused mainly on modification of lysine and arginine residues in proteins by reactive carbonyl intermediates formed during metabolism or autoxidation of carbohydrates and lipids (2,5). However, free cysteine is more abundant on intracellular proteins and, because of its greater nucleophilicity, is a more likely target for chemical modification by intracellular electrophiles.…”

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Succination of Thiol Groups in Adipose Tissue Proteins in Diabetes

Frizzell

Rajesh

Jepson

et al. 2009

Journal of Biological Chemistry

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S-(2-SuccinylWe show here that succination of protein is also increased in epididymal, mesenteric, and subcutaneous adipose tissue of diabetic (db/db) mice and that adiponectin is a major target for succination in both adipocytes and adipose tissue. Cys-39, which is involved in cross-linking of adiponectin monomers to form trimers, was identified as a key site of succination of adiponectin in adipocytes. 2SC was detected on two of seven monomeric forms of adiponectin immunoprecipitated from adipocytes and epididymal adipose tissue. Based on densitometry, 2SC-adiponectin accounted for ϳ7 and 8% of total intracellular adiponectin in cells and tissue, respectively. 2SC was found only in the intracellular, monomeric forms of adiponectin and was not detectable in polymeric forms of adiponectin in cell culture medium or plasma. We conclude that succination of adiponectin blocks its incorporation into trimeric and higher molecular weight, secreted forms of adiponectin. We propose that succination of proteins is a biomarker of mitochondrial stress and accumulation of Krebs cycle intermediates in adipose tissue in diabetes and that succination of adiponectin may contribute to the decrease in plasma adiponectin in diabetes.The accumulation of sugar and lipid-derived chemical modifications on proteins is associated with the etiology of several age-related diseases, including diabetes and its complications (1, 2). The irreversible adducts formed, termed advanced glycation/lipoxidation end products (AGE/ALEs), 2 accumulate over time on long lived proteins, such as collagens, affecting the solubility, elasticity, and proteolytic digestibility of the protein (3). AGE/ALEs are considered important mediators of the pathogenesis of diabetic complications through engagement of scavenger receptors, such as RAGE (receptor for AGE) and activation of proinflammatory signaling pathways (4). To date, the study of AGE/ALEs has focused mainly on modification of lysine and arginine residues in proteins by reactive carbonyl intermediates formed during metabolism or autoxidation of carbohydrates and lipids (2, 5). However, free cysteine is more abundant on intracellular proteins and, because of its greater nucleophilicity, is a more likely target for chemical modification by intracellular electrophiles.We recently identified S-(2-succinyl)-cysteine (2SC), a cysteine modification formed by a Michael addition reaction between the Krebs cycle intermediate fumarate and free sulfhydryl groups on proteins (6). This reaction, in which a thioether bond is formed, is described as succination of protein in order to distinguish it from succinylation, which leads to formation of amide, ester, or thioester bonds. 2SC was detected in human serum albumin and skin collagen and was increased in skeletal muscle protein and urine of diabetic rats. We also identified glyceraldehyde-3-phosphate dehydrogenase as one protein that is significantly modified by 2SC in skeletal muscle, resulting in the decrease in specific activity of glyceraldehyde-3-phosphate dehydr...

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Modification of Cysteine Residues in Protein by Endogenous Oxidants and Electrophiles

Frizzell

Baynes

2009

Endogenous Toxins

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Chemical modification of muscle protein in diabetes

Cited by 59 publications

References 19 publications

Advanced Glycation End Product in Diabetic Rat Skeletal Muscle in vivo

Advanced Glycation End Product in Diabetic Rat Skeletal Muscle in vivo

Succination of Thiol Groups in Adipose Tissue Proteins in Diabetes

Modification of Cysteine Residues in Protein by Endogenous Oxidants and Electrophiles

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