Isabelle Rieu

Leucine supplementation improves muscle protein synthesis in elderly men independently of hyperaminoacidaemia

The present study was designed to assess the effects of dietary leucine supplementation on muscle protein synthesis and whole body protein kinetics in elderly individuals. Twenty healthy male subjects (70 ± 1 years) were studied before and after continuous ingestion of a complete balanced diet supplemented or not with leucine. A primed (3.6 μmol kg−1) constant infusion (0.06 μmol kg−1 min−1) of l‐[1‐13C]phenylalanine was used to determine whole body phenylalanine kinetics as well as fractional synthesis rate (FSR) in the myofibrillar fraction of muscle proteins from vastus lateralis biopsies. Whole body protein kinetics were not affected by leucine supplementation. In contrast, muscle FSR, measured over the 5‐h period of feeding, was significantly greater in the volunteers given the leucine‐supplemented meals compared with the control group (0.083 ± 0.008 versus 0.053 ± 0.009% h−1, respectively, P < 0.05). This effect was due only to increased leucine availability because only plasma free leucine concentration significantly differed between the control and leucine‐supplemented groups. We conclude that leucine supplementation during feeding improves muscle protein synthesis in the elderly independently of an overall increase of other amino acids. Whether increasing leucine intake in old people may limit muscle protein loss during ageing remains to be determined.

A leucine-supplemented diet restores the defective postprandial inhibition of proteasome-dependent proteolysis in aged rat skeletal muscle

We tested the hypothesis that skeletal muscle ubiquitin–proteasome‐dependent proteolysis is dysregulated in ageing in response to feeding. In Experiment 1 we measured rates of proteasome‐dependent proteolysis in incubated muscles from 8‐ and 22‐month‐old rats, proteasome activities, and rates of ubiquitination, in the postprandial and postabsorptive states. Peptidase activities of the proteasome decreased in the postabsorptive state in 22‐month‐old rats compared with 8‐month‐old animals, while the rate of ubiquitination was not altered. Furthermore, the down‐regulation of in vitro proteasome‐dependent proteolysis that prevailed in the postprandial state in 8‐month‐old rats was defective in 22‐month‐old rats. Next, we tested the hypothesis that the ingestion of a 5% leucine‐supplemented diet may correct this defect. Leucine supplementation restored the postprandial inhibition of in vitro proteasome‐dependent proteolysis in 22‐month‐old animals, by down‐regulating both rates of ubiquitination and proteasome activities. In Experiment 2, we verified that dietary leucine supplementation had long‐lasting effects by comparing 8‐ and 22‐month‐old rats that were fed either a leucine‐supplemented diet or an alanine‐supplemented diet for 10 days. The inhibited in vitro proteolysis was maintained in the postprandial state in the 22‐month‐old rats fed the leucine‐supplemented diet. Moreover, elevated mRNA levels for ubiquitin, 14‐kDa ubiquitin‐conjugating enzyme E2, and C2 and X subunits of the 20S proteasome that were characteristic of aged muscle were totally suppressed in 22‐month‐old animals chronically fed the leucine‐supplemented diet, demonstrating an in vivo effect. Thus the defective postprandial down‐regulation of in vitro proteasome‐dependent proteolysis in 22‐month‐old rats was restored in animals chronically fed a leucine‐supplemented diet.

Reduction of low grade inflammation restores blunting of postprandial muscle anabolism and limits sarcopenia in old rats.

Ageing is characterized by a decline in muscle mass that could be explained by a defect in the regulation of postprandial muscle protein metabolism. Indeed, the stimulatory effect of food intake on protein synthesis and its inhibitory effect on proteolysis is blunted in old muscles from both animals and humans. Recently, low grade inflammation has been suspected to be one of the factors responsible for the decreased sensitivity of muscle protein metabolism to food intake. This study was undertaken to examine the effect of long‐term prevention of low grade inflammation on muscle protein metabolism during ageing. Old rats (20 months of age) were separated into two groups: a control group and a group (IBU) in which low grade inflammation had been reduced with a non‐steroidal anti inflammatory drug (ibuprofen). After 5 months of treatment, inflammatory markers and cytokine levels were significantly improved in treated old rats when compared with the controls: −22.3% fibrinogen, −54.2%α2‐macroglobulin, +12.6% albumin, −59.6% IL6 and −45.9% IL1β levels. As expected, food intake had no effect on muscle protein synthesis or muscle proteolysis in controls whereas it significantly increased muscle protein synthesis by 24.8% and significantly decreased proteolysis in IBU rats. The restoration of muscle protein anabolism at the postprandial state by controlling the development of low grade inflammation in old rats significantly decreased muscle mass loss between 20 and 25 months of age. In conclusion, the observations made in this study have identified low grade inflammation as an important target for pharmacological, nutritional and lifestyle interventions that aim to limit sarcopenia and muscle weakness in the rapidly growing elderly population in Europe and North America.

Is R2* a New MRI Biomarker for the Progression of Parkinson’s Disease? A Longitudinal Follow-Up

Purpose To study changes of iron content in basal ganglia in Parkinson’s disease (PD) through a three-year longitudinal follow-up of the effective transverse relaxation rate R2*, a validated MRI marker of brain iron content which can be rapidly measured under clinical conditions. Methods Twenty-seven PD patients and 26 controls were investigated by a first MRI (t0). Longitudinal analysis was conducted among the 18 controls and 14 PD patients who underwent a second MRI (t1) 3 years after. The imaging protocol consisted in 6 gradient echo images obtained at different echo-times for mapping R2*. Quantitative exploration of basal ganglia was performed by measuring the variation of R2* [R2*(t1) – R2*(t0)] in several regions of interest. Results During the three-year evolution of PD, R2* increased in Substantia nigra (SN) (by 10.2% in pars compacta, p = 0.001, and 8.1% in pars reticulata, p = 0.013) and in the caudal putamen (11.4%, p = 0.011), without significant change in controls. Furthermore, we showed a positive correlation between the variation of R2* and the worsening of motor symptoms of PD (p = 0.028). Conclusion Significant variation of R2* was longitudinally observed in the SN and caudal putamen of patients with PD evolving over a three-year period, emphasizing its interest as a biomarker of disease progression. Our results suggest that R2* MRI follow-up could be an interesting tool for individual assessment of neurodegeneration due to PD, and also be useful for testing the efficiency of disease-modifying treatments.

Glucocorticoid excess induces a prolonged leucine resistance on muscle protein synthesis in old rats

This experiment was undertaken to examine leucine responsiveness of muscle protein synthesis during dexamethasone treatment and the subsequent recovery in young (4-5 weeks), adult (10-11 months) and old rats (21-22 months). Rats received dexamethasone in their drinking water. The dose and length of the treatment was adapted in order to generate the same muscle atrophy. Protein synthesis was assessed in vitro by incorporation of radiolabelled phenylalanine into proteins at the end of the treatment and after 3 or 7-day recovery. Results showed that dexamethasone did not alter muscle protein synthesis stimulation by leucine in young rats. In contrast, muscles from adult and old rats became totally resistant to leucine. Furthermore, the recovery of leucine responsiveness after dexamethasone withdrawal was slowed down in old rats when compared to younger rats. We concluded that glucocorticoids exert their catabolic action in adult and old rats partly through antagonising the stimulatory effect of leucine and may contribute to sarcopenia in old rats.

Insulin and amino acids both strongly participate to the regulation of protein metabolism

Purpose of reviewThe application of tracer kinetic methods, combined with measurements of the activity of components of the cellular signaling pathways involved in protein synthesis and degradation, affords new insights into the regulation of skeletal muscle protein metabolism in vivo in humans. Feeding is associated with an increase in protein synthesis and a decrease in proteolysis. These changes are mediated by feeding-induced increases in plasma concentrations of both nutrients and hormones. Recent findingsRecent studies definitely demonstrated that insulin and amino acids directly interacted in promoting postprandial anabolism. However, the contribution of amino acids was abolished in old individuals in whom only insulin action persisted. There was a line of evidence that the effect of amino acids originates from leucine, which should not be viewed simply as a building block for protein synthesis, but as a signal in the regulation of cell functions. Although their cellular signaling pathways do not completely overlap, insulin and amino acids both activate the translation initiation of protein synthesis. Insulin presumably inhibits skeletal muscle protein degradation through a decrease in the activity of the ubiquitin proteasome-dependent pathway. SummaryWhether or not amino acids modify insulin action and have specific effects on proteolysis has not yet been documented. At the molecular level, amino acids such as insulin modulate gene expression. Such studies are needed to gain a better understanding of the interactions between insulin and amino acids in the regulation of skeletal muscle protein anabolism.

Deep Brain Stimulation of the Subthalamic Nucleus Regulates Postabsorptive Glucose Metabolism in Patients With Parkinson's Disease

OBJECTIVE Subthalamic nucleus-deep brain stimulation (STN-DBS) is an alternative treatment for patients with uncontrolled symptoms of Parkinsons disease (PD), but it has other nonmotor impact. Because STN-DBS alters the energy expenditure in humans, we hypothesized that STN-DBS may affect postabsorptive glucose metabolism in patients with PD. RESEARCH DESIGN AND METHODS Endogenous glucose production (EGP) and whole-body glucose disposal rates (GDRs) were assessed in the postabsorptive state during a primed continuous iv infusion of D-[6,6-(2)H2]glucose for 5 hours in 8 STN-DBS-treated patients with PD, without (Stim-OFF) and during STN-DBS (Stim-ON) treatment. EGP and GDR in PD patients were compared with glucose kinetics of 8 matched healthy control subjects. Plasma concentrations of insulin, glucagon, and free fatty acids were also determined. RESULTS EGP and GDR were higher in PD patients in Stim-OFF conditions than in the control group (2.62 ± 0.09 vs 2.27 ± 0.10 mg/kg·min, P < .05). Despite no significant changes in blood glucose throughout the kinetic study, a significant and consistent 22% decrease in EGP occurred in PD patients during Stim-ON (2.04 ± 0.07 mg/kg(-1)·min(-1); P < .01), and whole-body glucose kinetics in Stim-ON patients were no more different from those of the control subjects (P = NS). No difference in insulin, glucagon, or free fatty acid concentrations was observed in the patients between Stim-OFF and Stim-ON conditions. CONCLUSIONS Deep brain stimulation in patients with PD affects EGP glucose disposal, suggesting that a cross talk between the central nervous system and peripheral tissues may regulate glucose homeostasis.

Glucose dysregulation in Parkinson's disease: Too much glucose or not enough insulin?

OBJECTIVE To detect changes in glucose regulation in moderate to advanced Parkinsons disease (PD) patients in response to oral glucose intake. METHODS Blood glucose and insulin kinetics during a 75-g Oral Glucose Tolerance Test (OGTT) were compared between 50 PD patients and 50 healthy controls (CT) matched for body mass index (BMI), age and sex. Potential relationships between changes in glucose kinetics and clinical parameters were analyzed including Parkinsons disease severity and autonomic function using SCOPA-AUT (Scales for Outcomes in Parkinsons disease, Autonomic dysfunction). RESULTS Blood glucose was significantly higher at T90 (p = 0.04) and T150 (p = 0.01) in PD patients compared to healthy matched controls. Moreover, the total area under time curve (AUC) for the blood glucose levels was significantly higher in PD patients compared to healthy controls (1187 ± 229 vs 1101 ± 201 mmol min.l-1; p = 0.05). Simultaneously, no significant increase of insulin levels was observed in PD patients compared to controls. Higher blood glucose levels were associated with higher BMI (p < 0.001), female gender (p < 0.033), longer duration of PD (p = 0.001), lower dose of dopaminergic treatment (p = 0.023), and higher score of dysautonomia (p = 0.017). CONCLUSION Glucose control is impaired in moderate to advanced non-diabetic PD patients, due to impaired adaptive insulin response which may be a novel non-motor consequence of PD associated dysautonomia.