Supplementation-induced change in muscle carnosine is paralleled by changes in muscle metabolism, protein glycation and reactive carbonyl species sequestering

Carnosine is a performance-enhancing food supplement with a potential to modulate muscle energy metabolism and toxic metabolites disposal. In this study we explored interrelations between carnosine supplementation (2g/day, 12 weeks) induced effects on carnosine muscle loading and parallel changes in (i) muscle energy metabolism, (ii) serum albumin glycation and (iii) reactive carbonyl species sequestering in twelve (M/F=10/2) sedentary, overweight-to-obese (BMI: 30.0+/-2.7 kg/m2) adults (40.1+/-6.2 yrs). Muscle carnosine concentration (Proton Magnetic Resonance Spectroscopy; 1H-MRS), dynamics of muscle energy metabolism (Phosphorus Magnetic Resonance Spectroscopy; 31P-MRS), body composition (Magnetic Resonance Imaging; MRI), resting energy expenditure (indirect calorimetry), glucose tolerance (oGTT), habitual physical activity (accelerometers), serum carnosine and carnosinase-1 content/activity (ELISA), albumin glycation, urinary carnosine and carnosine-propanal concentration (mass spectrometry) were measured. Supplementation-induced increase in muscle carnosine was paralleled by improved dynamics of muscle post-exercise phosphocreatine recovery, decreased serum albumin glycation and enhanced urinary carnosine-propanal excretion (all p<0.05). Magnitude of supplementation-induced muscle carnosine accumulation was higher in individuals with lower baseline muscle carnosine, who had lower BMI, higher physical activity level, lower resting intramuscular pH, but similar muscle mass and dietary protein preference. Level of supplementation-induced increase in muscle carnosine correlated with reduction of protein glycation, increase in reactive carbonyl species sequestering, and acceleration of muscle post-exercise phosphocreatine recovery

CROP - The Clinico-Radiologico-Ophthalmological Paradox in Multiple Sclerosis: Are patterns of retinal and MRI changes heterogeneous and thus not predictable?

BACKGROUND: To date, no direct scientific evidence has been found linking tissue changes in multiple sclerosis (MS) patients, such as demyelination, axonal destruction or gliosis, with either steady progression and/or stepwise accumulation of focal CNS lesions. Tissue changes such as reduction of the retinal nerve fiber layer (RNFL) and the total macular volume (TMV), or brain- and spinal cord atrophy indicates an irreversible stage of tissue destruction. Whether these changes are found in all MS patients, and if there is a correlation with clinical disease state, remains controversial. The objective of our study was to determine, whether there was any correlation between the RNFL or TMV of patients with MS, and: (1) the lesion load along the visual pathways, (2) the ratios and absolute concentrations of metabolites in the normal-appearing white matter (NAWM), (3) standard brain atrophy indices, (4) disease activity or (5) disease duration.METHODS: 28 MS patients (RRMS, n = 23; secondary progressive MS (SPMS), n = 5) with moderately-high disease activity or long disease course were included in the study. We utilised: (1) magnetic resonance imaging (MRI) and (2) -spectroscopy (MRS), both operating at 3 Tesla, and (3) high-resolution spectral domain-OCT with locked reference images and eye tracking mode) to undertake the study.RESULTS: There was no consistency in the pattern of CNS metabolites, brain atrophy indices and the RNFL/TMV between individuals, which ranged from normal to markedly-reduced levels. Furthermore, there was no strict correlation between CNS metabolites, lesions along the visual pathways, atrophy indices, RNFL, TMV, disease duration or disability.CONCLUSIONS: Based on the findings of this study, we recommend that the concept of 'clinico-radiologico paradox' in multiple sclerosis be extended to CROP-'clinico-radiologico-ophthalmological paradox'. Furthermore, OCT data of MS patients should be interpreted with caution.</p

Correlation between skeletal muscle acetylcarnitine and phosphocreatine metabolism during submaximal exercise and recovery: interleaved 1H/31P MRS 7 T study

Abstract Acetylcarnitine is an essential metabolite for maintaining metabolic flexibility and glucose homeostasis. The in vivo behavior of muscle acetylcarnitine content during exercise has not been shown with magnetic resonance spectroscopy. Therefore, this study aimed to explore the behavior of skeletal muscle acetylcarnitine during rest, plantar flexion exercise, and recovery in the human gastrocnemius muscle under aerobic conditions. Ten lean volunteers and nine overweight volunteers participated in the study. A 7 T whole-body MR system with a double-tuned surface coil was used to acquire spectra from the gastrocnemius medialis. An MR-compatible ergometer was used for the plantar flexion exercise. Semi-LASER-localized 1H MR spectra and slab-localized 31P MR spectra were acquired simultaneously in one interleaved exercise/recovery session. The time-resolved interleaved 1H/31P MRS acquisition yielded excellent data quality. A between-group difference in acetylcarnitine metabolism over time was detected. Significantly slower τPCr recovery, τPCr on-kinetics, and lower Qmax in the overweight group, compared to the lean group was found. Linear relations between τPCr on-kinetics, τPCr recovery, VO2max and acetylcarnitine content were identified. In conclusion, we are the first to show in vivo changes of skeletal muscle acetylcarnitine during acute exercise and immediate exercise recovery with a submaximal aerobic workload using interleaved 1H/31P MRS at 7 T

International Journal of Endocrinology / Pericardial Fat Relates to Disturbances of Glucose Metabolism in Women with the Polycystic Ovary Syndrome, but Not in Healthy Control Subjects

Objective The objective of the present study is to investigate the relationship of cardiac fat depots with disturbances of the carbohydrate metabolism in women with PCOS. Methods An oral glucose tolerance test (OGTT) was realized, and metabolic parameters were collected in 48 women with PCOS and in 20 controls. Intramyocardial fat (MYCL) and pericardial fat (PERI) were measured using 1H-magnetic resonance spectroscopy and imaging. Results Only in PCOS women, PERI was positively and independently related to parameters of glucose metabolism (HbA1c: p = 0 001, fasting plasma glucose: p < 0 001, stimulated glucose at 30 and 60 minutes in the OGTT). Thus, the disposition index, insulin sensitivity, and adiponectin also declined with the increase of PERI in women with PCOS; however, these results were not independent of BMI and age. In addition, PERI was positively related to atherogenic lipid profiles, BMI, waist circumference, CRP, and liver fat in women with PCOS. A negative relation of PERI with triglycerides and a positive relation with BMI and waist circumference could be observed in the controls. No relationship of MYCL with diabetes-specific parameters could be found in the study population. Conclusion PERI is related to metabolic disturbances in women with PCOS, but not in metabolically healthy lean subjects. This clinical trial was registered at ClinicalTrials.gov and has the registration number NCT03204461.(VLID)470864

RNFL in MS patients.

<p><b>Retinal sectors: OD</b>, right eye; <b>OS</b>, left eye; <b>G</b>, global; <b>S</b>, superior; <b>I</b>, inferior; <b>T</b>, temporal; <b>TS</b>, temporal superior; <b>TI</b>, temporal inferior; <b>N</b>, nasal; <b>NS</b>, nasal superior; <b>NI</b>, nasal inferior. All values are given in μm.</p><p>RNFL in MS patients.</p

Metabolites in NAWM and lesion load in the visual pathways in MS patients.

<p><b>Metabolites</b>, N-Acetyl-Aspartate (NAA), Choline (Cho) and creatine (Cr) given in mM; <b>lesion load in the visual pathways</b>, here given as ratio of lesion volume in the visual pathways (AD, right anterior; AS, left anterior; PD, right posterior; PS, left posterior and total lesion volume) to total brain volume.</p><p>Metabolites in NAWM and lesion load in the visual pathways in MS patients.</p

Brain atrophy indices in MS patients.

<p><b>CHI</b>, the caudate head index; <b>BCI</b>, the basal cistern index; <b>CMI</b>, the cella media index; <b>MIF</b>, the maximum width of the anterior interhemispheric fissure; <b>MSF</b>, the maximum width of the Sylvian fissure; and <b>MFSS</b>, the maximum frontal subarachnoid space.</p><p>Brain atrophy indices in MS patients.</p

Regression Analysis.

<p><u>Simple regression–linear model: Independent variable</u>, RNFL; <u>dependent variables</u>, NAA, N-acetyl-aspartate; Cho, choline; Cr, creatine; LL per BV, lesionload per Brain Volume, LL AR, lesion load along anterior right visual pathway; LL AL, lesion load along anterior left visual pathway; LL PR, load along posterior right visual pathway; LL PL, load along posterior left visual pathway; Evan’s Index; CHI; CMI; BCI; the maximum width of the 3^rd ventricle; the maximum width of the 4^th ventricle; MIF, the maximum width of the anterior interhemispheric fissure; MFSS, the maximum frontal subarachnoid space; MSF, the maximum width of the Sylvian fissure; DD, disease duration; EDSS, expanded disability severity scale. <b>1</b>^<b>st</b><b>row</b>: all right eyes (n = 28; with and without ON) of all included MS patient. <b>2</b>^<b>nd</b><b>row</b>: all left eyes (n = 28; with and without ON) of all included MS patient. <b>3</b>^<b>rd</b><b>row</b>: all right eyes of MS patients who never experienced an ON (neither on their right nor on their left eye; RRMS, n = 17, SPMS, n = 2; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.t001" target="_blank">Table 1</a>). <b>4</b>^<b>th</b><b>row</b>: all left eyes of MS patients who never experienced an ON (neither on their left nor on their right eye; RRMS, n = 17, SPMS, n = 2; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.t001" target="_blank">Table 1</a>). Patients are the same as in the 3^rd row. <b>5</b>^<b>th</b><b>row</b>: right eyes of 6 MS patients who experienced an ON on their right eyes (note, 4 out of 6 experienced ON on both eyes, 2 only on their right eyes; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.t001" target="_blank">Table 1</a>). <b>6</b>^<b>th</b><b>row</b>: left eyes of 6 MS patients who experienced an ON on their left eyes (note, 4 out of 7 experienced ON on both eyes, 3 only on their left eyes <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.t001" target="_blank">Table 1</a>). For each analysis the correlation coefficient (corr. coeff.), R-squared (percent), the standard error of estimate (STE of Est.) and the p-value (analysis of variance, ANOVA) is given. Since the p-value in the ANOVA table is less than 0.01, there is a statistically significant relationship between the maximum width of the 4^th ventricle and the RNFL (for all patients’ right eyes, n = 28, 1^st row and for all patient’s left eyes, who never experienced ON, n = 17, 4^th row) at 99% confidence level. However, the low correlation coefficient indicates that there is only a weak relationship between the variables. R-squared statistic indicates that the simple/linear regression explains only 24.92% (1^st row) or 28.68% (4^th row) of the variability of the independent variable. In all other analyses presented here (and performed for the six OCT-Sectors, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#sec006" target="_blank">material and methods</a> or <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.t005" target="_blank">Table 5</a>) no statistically significant correlation could be found (data not shown).</p

Clinical data.

<p><b>ON</b>, <b>optic neuritis;</b></p><p><b>*</b>, relapses treated with high dose steroid pulse therapy; no included patient had an ON within 12 months prior to the beginning of the study;</p><p><b>GLAT</b>, glatiramer-acetate 20mg subcutaneous once daily; <b>MITOX</b>, mitoxantrone; <b>IFN(a)</b>, interferon beta 1a intramuscularly once per week; <b>IFN(b)</b>, interferon beta 1a (44μg) subcutaneous trice per week; <b>IFN(c)</b>, interferon beta 1b (250μg) subcutaneous alternate day. Most importantly, the disease activity remained high in further follow-up with a median observation period of 22 ± 0.5 months [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.ref033" target="_blank">33</a>]. However, no significant reduction of either the RNFL or the TMV could be found in follow-up [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.ref033" target="_blank">33</a>; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142272#pone.0142272.ref036" target="_blank">36</a>].</p><p>¹, discontinued (48mg mitoxantrone per m² body surface); <b>none</b>, neither specific immunomodulatory or immunsuppressive therapy, drug holiday;</p><p>², drug withdrawal 12 months before OCT examination;</p><p>³, drug withdrawal 6 months before OCT examination;</p><p>⁴, drug withdrawal 20 months before OCT examination;</p><p>⁵, high titres of anti-interferon autoantibodies, drug withdrawal 14 months before OCT examination;</p><p>⁶, mitoxantrone cumulative dose 96mg per m² body surface, drug withdrawal 10 months before OCT examination;</p><p>⁷, mitoxantrone cumulative dose 92mg per m² body surface, drug withdrawal 10 months before OCT examination;</p><p>⁸, mitoxantrone cumulative dose 92mg per m² body surface, drug withdrawal 26 months before OCT examination;</p><p>⁹, mitoxantrone cumulative dose 108mg per m² body surface, drug withdrawal 27 months before 1^st OCT examination.</p><p>Clinical data.</p