Exercise alters and beta-alanine combined with exercise augments histidyl dipeptide levels and scavenges lipid peroxidation products in human skeletal muscle

Title on article: Exercise alters and β-alanine combined with exercise augments histidyl dipeptide levels and scavenges lipid peroxidation products in human skeletal muscl

Integrated Multilayer Omics Reveals the Genomic, Proteomic, and Metabolic Influences of Histidyl Dipeptides on the Heart

Background: Histidyl dipeptides such as carnosine are present in a micromolar to millimolar range in mammalian hearts. These dipeptides facilitate glycolysis by proton buffering. They form conjugates with reactive aldehydes, such as acrolein, and attenuate myocardial ischemia-reperfusion injury. Although these dipeptides exhibit multifunctional properties, a composite understanding of their role in the myocardium is lacking. Methods and Results: To identify histidyl dipeptide-mediated responses in the heart, we used an integrated triomics approach, which involved genome-wide RNA sequencing, global proteomics, and unbiased metabolomics to identify the effects of cardiospecific transgenic overexpression of the carnosine synthesizing enzyme, carnosine synthase (Carns), in mice. Our result showed that higher myocardial levels of histidyl dipeptides were associated with extensive changes in the levels of several microRNAs, which target the expression of contractile proteins, β-fatty acid oxidation, and citric acid cycle (TCA) enzymes. Global proteomic analysis showed enrichment in the expression of contractile proteins, enzymes of β-fatty acid oxidation, and the TCA in the Carns transgenic heart. Under aerobic conditions, the Carns transgenic hearts had lower levels of short- and long-chain fatty acids as well as the TCA intermediate-succinic acid; whereas, under ischemic conditions, the accumulation of fatty acids and TCA intermediates was significantly attenuated. Integration of multiple data sets suggested that β-fatty acid oxidation and TCA pathways exhibit correlative changes in the Carns transgenic hearts at all 3 levels. Conclusions: Taken together, these findings reveal a central role of histidyl dipeptides in coordinated regulation of myocardial structure, function, and energetics

Carnosinase-1 overexpression, but not aerobic exercise training, affects the development of diabetic nephropathy in BTBR ob/ob mice

Manipulation of circulating histidine-containing dipeptides (HCD) has been shown to affect the development of diabetes and early-stage diabetic nephropathy (DN). The aim of the present study was to investigate whether such interventions, which potentially alter levels of circulating HCD, also affect the development of advanced-stage DN. Two interventions, aerobic exercise training and overexpression of the human carnosinase-1 (hCN1) enzyme, were tested. BTBR ob/ob mice were either subjected to aerobic exercise training (20 wk) or genetically manipulated to overexpress hCN1, and different diabetes- and DN-related markers were compared with control ob/ob and healthy (wild-type) mice. An acute exercise study was performed to elucidate the effect of obesity, acute running, and hCN1 overexpression on plasma HCD levels. Chronic aerobic exercise training did not affect the development of diabetes or DN, but hCN1 overexpression accelerated hyperlipidemia and aggravated the development of albuminuria, mesangial matrix expansion, and glomerular hypertrophy of ob/ob mice. In line, plasma, kidney, and muscle HCD were markedly lower in ob/ob versus wild-type mice, and plasma and kidney HCD in particular were lower in ob/ob hCN1 versus ob/ob mice but were unaffected by aerobic exercise. In conclusion, advanced glomerular damage is accelerated in mice overexpressing the hCN1 enzyme but not protected by chronic exercise training. Interestingly, we showed, for the first time, that the development of DN is closely linked to renal HCD availability. Further research will have to elucidate whether the stimulation of renal HCD levels can be a therapeutic strategy to reduce the risk for developing DN

What lies between market and hierarchy? Insights from internalization theory and global value chain theory

In this paper, we suggest that internalization theory might be extended by incorporating complementary insights from GVC theory. More specifically, we argue that internalization theory can explain why lead firms might wish to externalize selected activities, but that it is largely silent on the mechanisms by which those lead firms might exercise control over the resultant externalized relationships with their GVC partners. We advance an explanation linking the choice of control mechanism to two factors: power asymmetries between the lead firms and their GVC partners, and the degree of codifiability of the information to be exchanged in the relationship

Urinary Levels of the Acrolein Conjugates of Carnosine Are Associated with Cardiovascular Disease Risk

Carnosine is a naturally occurring dipeptide (β-alanine-L-histidine) which supports physiological homeostasis by buffering intracellular pH, chelating metals, and conjugating with and neutralizing toxic aldehydes such as acrolein. However, it is not clear if carnosine can support cardiovascular function or modify cardiovascular disease (CVD) risk. To examine this, we measured urinary levels of nonconjugated carnosine and its acrolein conjugates (carnosine-propanal and carnosine-propanol) in participants of the Louisville Healthy Heart Study and examined associations with indices of CVD risk. We found that nonconjugated carnosine was significantly associated with hypertension (p = 0.011), heart failure (p = 0.015), those categorized with high CVD risk (p p = 0.007), high sensitivity C-reactive protein (hsCRP; p = 0.026), high-density lipoprotein (HDL; p = 0.007) and certain medication uses. Levels of carnosine-propanal and carnosine-propanol demonstrated significant associations with BMI, blood glucose, HDL and diagnosis of diabetes. Carnosine-propanal was also associated with heart failure (p = 0.045) and hyperlipidemia (p = 0.002), but no associations with myocardial infarction or stroke were identified. We found that the positive associations of carnosine conjugates with diabetes and HDL remain statistically significant (p < 0.05) in an adjusted, linear regression model. These findings suggest that urinary levels of nonconjugated carnosine, carnosine-propanal and carnosine-propanol may be informative biomarkers for the assessment of CVD risk—and particularly reflective of skeletal muscle injury and carnosine depletion in diabetes

Exercise alters and β-alanine combined with exercise augments histidyl dipeptide levels and scavenges lipid peroxidation products in human skeletal muscle

Carnosine and anserine are dipeptides synthesized from histidine and β-alanine by carnosine synthase (ATPGD1). These dipeptides, present in high concentration in the skeletal muscle, form conjugates with lipid peroxidation products such as 4-hydroxy trans-2-nonenal (HNE). Although skeletal muscle levels of these dipeptides could be elevated by feeding β-alanine, it is unclear how these dipeptides and their conjugates are affected by exercise training with or without β-alanine supplementation. We recruited twenty physically active men, who were allocated to either β-alanine or placebo-feeding group matched for VO2 peak, lactate threshold, and maximal power (Wmax). Participants completed 2 weeks of conditioning phase followed by 1 week of exercise testing (CPET) and a single session followed by 6 weeks of high intensity interval training (HIIT). Analysis of muscle biopsies showed that the levels of carnosine and ATPGD1 expression were increased after CPET and decreased following a single session and 6 weeks of HIIT. Expression of ATPGD1 and levels of carnosine were increased upon β-alanine-feeding after CPET, while ATPGD1 expression decreased following a single session of HIIT. The expression of fiber type markers myosin heavy chain (MHC) I and IIa remained unchanged after CPET. Levels of carnosine, anserine, carnosine-HNE, carnosine-propanal and carnosine-propanol were further increased after 9 weeks of β-alanine supplementation and exercise training, but remained unchanged in the placebo-fed group. These results suggest that carnosine levels and ATPGD1 expression fluctuates with different phases of training. Enhancing carnosine levels by β-alanine feeding could facilitate the detoxification of lipid peroxidation products in the human skeletal muscle

Skeletal muscle analysis of cancer patients reveals a potential role for carnosine in muscle wasting

Abstract Background Muscle wasting during cancer cachexia is mediated by protein degradation via autophagy and ubiquitin‐linked proteolysis. These processes are sensitive to changes in intracellular pH ([pH]i) and reactive oxygen species, which in skeletal muscle are partly regulated by histidyl dipeptides, such as carnosine. These dipeptides, synthesized by the enzyme carnosine synthase (CARNS), remove lipid peroxidation‐derived aldehydes, and buffer [pH]i. Nevertheless, their role in muscle wasting has not been studied. Methods Histidyl dipeptides in the rectus abdominis (RA) muscle and red blood cells (RBCs) of male and female controls (n = 37), weight stable (WS: n = 35), and weight losing (WL; n = 30) upper gastrointestinal cancer (UGIC) patients, were profiled by LC–MS/MS. Expression of enzymes and amino acid transporters, involved in carnosine homeostasis, was measured by Western blotting and RT‐PCR. Skeletal muscle myotubes were treated with Lewis lung carcinoma conditioned medium (LLC CM), and β‐alanine to study the effects of enhancing carnosine production on muscle wasting. Results Carnosine was the predominant dipeptide present in the RA muscle. In controls, carnosine levels were higher in men (7.87 ± 1.98 nmol/mg tissue) compared with women (4.73 ± 1.26 nmol/mg tissue; P = 0.002). In men, carnosine was significantly reduced in both the WS (5.92 ± 2.04 nmol/mg tissue, P = 0.009) and WL (6.15 ± 1.90 nmol/mg tissue; P = 0.030) UGIC patients, compared with controls. In women, carnosine was decreased in the WL UGIC (3.42 ± 1.33 nmol/mg tissue; P = 0.050), compared with WS UGIC patients (4.58 ± 1.57 nmol/mg tissue), and controls (P = 0.025). Carnosine was significantly reduced in the combined WL UGIC patients (5.12 ± 2.15 nmol/mg tissue) compared with controls (6.21 ± 2.24 nmol/mg tissue; P = 0.045). Carnosine was also significantly reduced in the RBCs of WL UGIC patients (0.32 ± 0.24 pmol/mg protein), compared with controls (0.49 ± 0.31 pmol/mg protein, P = 0.037) and WS UGIC patients (0.51 ± 0.40 pmol/mg protein, P = 0.042). Depletion of carnosine diminished the aldehyde‐removing ability in the muscle of WL UGIC patients. Carnosine levels were positively associated with decreases in skeletal muscle index in the WL UGIC patients. CARNS expression was decreased in the muscle of WL UGIC patients and myotubes treated with LLC‐CM. Treatment with β‐alanine, a carnosine precursor, enhanced endogenous carnosine production and decreased ubiquitin‐linked protein degradation in LLC‐CM treated myotubes. Conclusions Depletion of carnosine could contribute to muscle wasting in cancer patients by lowering the aldehyde quenching abilities. Synthesis of carnosine by CARNS in myotubes is particularly affected by tumour derived factors and could contribute to carnosine depletion in WL UGIC patients. Increasing carnosine in skeletal muscle may be an effective therapeutic intervention to prevent muscle wasting in cancer patients