Muscle protein catabolism in diabetes: 3-Methylhistidine excretion in the spontaneously diabetic “BB” rat

doi:10.1016/0026-0495(80)90158-4

Metabolism

Volume 29, Issue 12, December 1980, Pages 1272-1277

https://doi.org/10.1016/0026-0495(80)90158-4 Get rights and content

Abstract

The muscle protein lost in uncontrolled diabetes may be due to decreased synthesis, increased catabolism, or to any combination of alteration in these rates that results in net loss. Differing methods of examining these rates in vivo and in vitro have given conflicting results. We assessed the rate of catabolism of proteins containing 3-methylhistidine (3-MH) by measurement of its urinary excretion in spontaneously diabetic “BB” Wistar rats. Prior to overt diabetes, rates of excretion were appropriate to the age of the rats (1.46 ± 0.15 μmole/day), with 34%–47% as the nonacetylated form. Accompanying diabetes there was an increase in urine urea nitrogen of two to threefold over 4–14 days, and an increase in ammonium nitrogen of sixfold. 3-MH excretion doubled by 4 days, and 81%–96% was excreted as the nonacetylated form. Subcutaneous insulin in doses sufficient to improve glycosuria and hyperglycemia was associated with normalized total 3-MH excretion (N-acetyl 3-MH plus 3-MH) but a greater proportion than normal appeared in the nonacetylated form. These results suggest that muscle protein catabolism increased with insulin deficiency and that this defect can be corrected by therapy. Both untreated and treated diabetic rats appear to have a limited capacity for acetylation of 3-MH prior to its excretion.

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The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass
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In type I diabetic patients muscle proteolysis was demonstrated by increased leucine flux and oxidation [69]. Also, in diabetic BB rats, urinary excretion of 3-methylhistidine, a non-metabolized amino acid found exclusively in contractile proteins, was found to be increased and was normalized by insulin treatment [70]. In addition, assessment of body composition of 2675 older adults revealed that type II diabetes is also associated with excessive loss of skeletal muscle [71].
The ubiquitin–proteasome system (UPS) is the main regulatory mechanism of protein degradation in skeletal muscle. The ubiquitin-ligase enzymes (E3s) have a central role in determining the selectivity and specificity of the UPS. Since their identification in 2001, the muscle specific E3s, muscle RING finger-1 (MuRF-1) and muscle atrophy F-box (MAFbx), have been shown to be implicated in the regulation of skeletal muscle atrophy in various pathological and physiological conditions. This review aims to explore the involvement of MuRF-1 and MAFbx in catabolism of skeletal muscle during various pathologies, such as cancer cachexia, sarcopenia of aging, chronic kidney disease (CKD), diabetes, and chronic obstructive pulmonary disease (COPD). In addition, the effects of various lifestyle and modifiable factors (e.g. nutrition, exercise, cigarette smoking, and alcohol) on MuRF-1 and MAFbx regulation will be discussed. Finally, evidence of potential strategies to protect against skeletal muscle wasting through inhibition of MuRF-1 and MAFbx expression will be explored.
Upregulation of osteopontin gene expression in diabetic rat proximal tubular cells revealed by microarray profiling
2006, Kidney International
Citation Excerpt :
The rat TGF-β1 cDNA with NotI restriction enzyme site attached at both 5′ and 3′ termini was subsequently subcloned into the NotI site of the expression vector pcDNA 3.1 (InVitrogen, Inc.) in sense and antisense orientation. Two animal models of insulin-dependent diabetes (type I) were employed: spontaneously diabetic BB rats and STZ-induced diabetic Wistar rats.41-45 Adult (60-day old) male BB rats were purchased from Health Canada (Ottawa, ON, Canada), acclimatized for 2 days, and blood sugar levels were measured every other day (Accu-Check Compact, Roche Diagnostics, Laval, QC, Canada).
Progression of diabetic nephropathy appears directly related to renal tubulointerstitial injury, but the involved genes are incompletely delineated. To identify such genes, DNA microarray analysis was performed with RNA from renal proximal tubules (RPTs) of streptozotocin-induced diabetic Wistar rats, spontaneously diabetic BioBreeding rats, and rat immortalized renal proximal tubular cells (IRPTCs) exposed to high glucose (25 mM) medium for 2 weeks. Osteopontin (OPN) mRNA expression was quantified by real time-quantitative polymerase chain reaction (RT-qPCR) or conventional reverse transcriptase-polymerase chain reaction (RT-PCR). OPN mRNA expression was upregulated (5–70-fold increase) in diabetic rat RPTs and in IRPTCs chronically exposed to high glucose compared to control RPTs and IRPTCs. High glucose, angiotensin II, phorbol 12-myristate 13-acetate and transforming growth factor-beta 1 (TGF-β₁) stimulated OPN mRNA expression in IRPTCs in a dose- and time-dependent manner. This effect was inhibited by tiron, taurine, diphenylene iodinium, losartan, perindopril, calphostin C, or LY 379196 but not PD123319. IRPTCs overexpressing dominant-negative protein kinase C-beta 1 (PKC-β₁) cDNA or antisense TGF-β₁ cDNA prevented the high glucose effect on OPN mRNA expression. We concluded that high glucose-mediated increases in OPN gene expression in diabetic rat RPTs and IRPTCs are mediated, at least in part, via reactive oxygen species generation, intrarenal rennin–angiotensin system activation, TGF-β₁ expression, and PKC-β₁ signaling.
Insulin suppresses the increased activities of lysosomal cathepsins and ubiquitin conjugation system in burn-injured rats
2000, Journal of Surgical Research
Background. Burn injury results in increased rate of skeletal muscle protein degradation. In vitro studies on incubated muscles indicate that increased rate of protein degradation is due to activation of multiple proteolytic systems, but the supporting evidence is of an indirect nature. The present study was carried out to investigate the role of various lysosomal cathepsins, ubiquitin conjugation, and proteasome systems in accelerated proteolysis, and the effect of insulin in burn-induced muscle wasting syndrome.
Materials and methods. Fifteen to twenty percent total body surface area scald burn injury was inflicted on the shaved dorsum of young growing rats. Insulin-treated rats received a daily single subcutaneous injection for 3 days (0.25–1.0 U/day). The rate of ubiquitin conjugation to endogenous proteins and exogenously added ¹²⁵I-lysozyme and the activities of various proteases were measured in muscle homogenates.
Results. Burn injury resulted in increased rate of ubiquitin conjugation to endogenous proteins and ¹²⁵I-lysozyme. Activities of cathepsins B, C, H, and L were also up-regulated following burn injury. When the burn-injured rats were treated with insulin, the increased rate of ubiquitin conjugation and cathepsin activities were suppressed to the control levels.
Conclusions. The increased ubiquitin conjugation and lysosomal cathepsins contribute to accelerated protein degradation in burn-injured rats and insulin suppresses the muscle protein degradation at least in part by suppressing the activities of lysosomal cathepsins and of ubiquitin conjugation system.
Value and limitations of 3-methyl-histidine assay for muscle catabolism assessment
1992, Nutrition clinique et metabolisme
La mesure de l'excrétion urinaire de 3-méthylhistidine est reconnue depuis longtemps comme un marqueur du catabolisme musculaire. Alors que certains facteurs restrictifs, comme l'importance de l'origine exogène ou la part provenant du territoire splanchnique, ont été avancés pour en limiter l'importance, certains travaux récents ont montré que ce paramètre restait d'un grand intérêt pour l'estimation du catabolisme musculaire au prix de quelques précautions. L'utilisation du rapport 3-méthylhistidine (μmol/l)/créatinine (mmol/l) permet de réduire les différences interindividuelles et surtout de s'affranchir de la nécessité d'un recueil complet de la diurèse des 24 heures. Si, en pratique clinique courante, la détermination du niveau de l'hypercatabolisme protéique repose avant tout sur la mesure de l'excrétion urinaire d'urée ou d'azote, la mesure du rapport 3-méthylhistidine/créatinine garde beaucoup d'intérêt lorsque le recueil complet des urines des 24 heures est aléatoire ou impossible, chez les patients hypercataboliques et dénutris, et pour l'appréciation de l'efficacité des apports nutritionnels. Bien sûr, en recherche clinique la mesure du catabolisme musculaire à l'aide de ce paramètre reste d'un intérêt primordial.
3-methylhistidine has long been used as a marker of muscle protein breakdown. Although certain factors such as exogenous intake and gastrointestinal synthesis may limit its validity, recent publications suggest that 3-methylhistidine is still a valuable index of muscle protein catabolism. The use of the 3-methylhistidine (μmol/l)/creatinine (mmol/l) ratio can limit interindividual variations and provide useful information, even when 24 h urine collection is incomplete. Although in clinical practice the measurement of urinary urea or nitrogen is the main parameter used to quantify the hypercatabolic response to acute illness, the 3-methylhistidine/creatinine ratio is of value when 24 h urine collections are incomplete, as well as in hypercatabolic patients with severe protein-calorie malnutrition and for evaluating the quality of nutritional support. Needless to say, this parameter remains crucial for the determination of muscle protein catabolism in clinical research.
Rat muscle protein turnover and redox state in progressive diabetes
1987, Life Sciences
Protein synthesis and degradation, and redox state were measured in soleus and extensor digitorum longus muscles of rats up to 12 days after injection of streptozotocin. Muscle growth was slower in these animals apparently due to slower protein synthesis throughout the duration of diabetes. Up to day 4 after injection of streptozotocin or withdrawal of insulin from treated, diabetic animals, the muscle ratio of lactate/pyruvate, an indicator of the cytoplasmic NAD⁺ redox couple, was lower and protein degradation was faster than in control muscles. Thereafter, the ratio of lactate/pyruvate was greater and protein degradation was slower than in size- or age-matched control muscles. Insulin treatment $in$ $vitro$ or $in$ $vivo$ increased lactate/pyruvate and decreased proteolysis. Therefore, in muscles of streptozotocin-diabetic rats, the initial increase and later fall in proteolysis, and the inhibition of proteolysis by insulin, may correlate with opposite changes in NADH/NAD⁺.
Sulfur amino acid metabolism in juvenile-onset nonketotic and ketotic diabetic patients
1984, Metabolism
Sulfur amino acid metabolism was studied in non-fasting nonketotic and ketotic juvenile-onset diabetic children and the results were compared to age-matched healthy children on an ordinary diet. An increased excretion of total sulfur and inorganic sulfate was found in diabetic children, probably a result of a decreased protein-serum synthesis and/or increased endogenous protein catabolism, although as a result of hyperglycemia a decreased tubular reabsorption may also have contributed. All diabetics showed a normal excretion of methionine. For cyst(e)ine and taurine an increased excretion was seen in ketotic diabetics, probably also a consequence of an increased endogenous protein degradation. As a sign of the latter, an increased output of 3-methylhistidine was also observed, a confirmation of earlier reports. The increased output of mercaptolactate and mercaptoacetate found in ketotic patients, was probably also a result of enhanced endogenous protein degradation. An increased urinary excretion of N-acetylcysteine was seen in diabetic children, which may reflect an enhanced availability to acetyl coenzyme A.

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^☆: Supported in part by grants from the Medical Research Council of Canada (MA 6540), and the National Institutes of Health (AM 25371).

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Muscle protein catabolism in diabetes: 3-Methylhistidine excretion in the spontaneously diabetic “BB” rat☆

Abstract

J Biol Chem

J Biol Chem

J Biol Chem

Am J Clin Nutr

J Biol Chem

Metabolism

J Nutr

On diabetic ketoacidosis: A detailed study of electrolyte balances following the withdrawal and re-establishment of insulin therapy

J Clin Invest

Protein metabolism

The relative importance of muscle protein synthesis and breakdown in the regulation of muscle mass

Biochem J

Intracellular protein degradation and its regulation by hormones and nutrients