Biomedical subjects

Pascal Sirvent

Publications and source records attributed to Pascal Sirvent.

7 recordsLinked to original sources

PubMed2006

Differential localization of autolyzed calpains 1 and 2 in slow and fast skeletal muscles in the early phase of atrophy.

Calpains have been proposed to be involved in the cytoskeletal remodeling and wasting of skeletal muscle. However, limited data are available about the specific involvement of each calpain in the early stages of muscle atrophy. The aims of this study were to determine whether calpains 1 and 2 are autolyzed after a short period of muscle disuse, and, if so, where in the myofibers the autolyzed products are localized. In the rat soleus muscle, 5 days of immobilization increased autolyzed calpain 1 in the particulate and not the soluble fraction. Conversely, autolyzed calpain 2 was not found in the particulate fraction, whereas it was increased in the soluble fraction after immobilization. In the less atrophied plantaris muscle, no difference was noted between the control and immobilized groups whatever the fraction or calpain. Other proteolytic pathways were also investigated. The ubiquitin-proteasome pathway was activated in both skeletal muscles, and caspase 3 was activated only in the soleus muscle. Taken together, our data suggest that calpains 1 and 2 are involved in atrophy development in slow type muscle exclusively and that they have different regulation and protein targets. Moreover, the activation of proteolytic pathways appears to differ in slow and fast muscles, and the proteolytic mechanisms involved in fast-type muscle atrophy remain unclear.

Animals↗

PubMed2005

Simvastatin induces impairment in skeletal muscle while heart is protected.

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are widely used to reduce plasma cholesterol concentration. However, statins are also known to induce various forms of muscular toxicity. We have previously shown that acute application of simvastatin on human skeletal muscle samples induced a cascade of cellular events originating from mitochondria and resulting in a global alteration of Ca2+ homeostasis. The present study was designed to further define the origin of the mitochondria impairment and to understand the apparent lack of deleterious effect on the heart. Using fluorescence imaging analysis and oxygraphy on human and rat skinned skeletal muscle samples, we show that the simvastatin-induced mitochondria impairment results from inhibition of the complex I of respiratory chain. Similar simvastatin-induced mitochondria impairment and alteration of Ca2+ homeostasis occur in permeabilized but not in intact ventricular rat cardiomyocytes. In intact rat skeletal muscle fibers from the flexor digitorum brevis muscle, the simvastatin-induced alteration of Ca2+ homeostasis is abolished when monocarboxylate transporter (MCT4) is inhibited. The impairment of complex I by simvastatin might be the primary step of its cellular deleterious effects leading to muscle fiber death. This mechanism is seen specifically in skeletal muscles. This specificity should be in part attributed to a preferential uptake of statins by MCT4 that is not expressed in cardiomyocytes.

Animals↗

PubMed2005

Endurance training increases lactate transport in male Zucker fa/fa rats.

The purpose of this study was to investigate the effect of endurance training (10 weeks) on previously reported alterations of lactate exchange in obese Zucker fa/fa rats. We used sarcolemmal vesicles to measure lactate transport capacity in control sedentary rats, Zucker (fa/fa), and endurance trained Zucker (fa/fa) rats. Monocarboxylate transporter (MCT) 1 and 4 content was measured in sarcolemmal vesicles and skeletal muscle. Training increased citrate synthase activity in soleus and in red tibialis anterior, and improved insulin sensitivity measured by intraperitoneal glucose tolerance test. Endurance training increased lactate influx in sarcolemmal vesicles at 1 mM of external lactate concentration and increased MCT1 expression on sarcolemmal vesicles. Furthermore, muscular lactate level was significantly decreased after training in red tibialis anterior and extensor digitorum longus. This study shows that endurance training improves impairment of lactate transport capacity that is found in insulin resistance state like obesity and type 2 diabetes.

Amino Acid Sequence↗

PubMed2005

Simvastatin triggers mitochondria-induced Ca2+ signaling alteration in skeletal muscle.

Statin drugs represent the major improvement in the treatment of hypercholesterolemia that constitutes the main origin of atherosclerosis, leading to coronary heart disease. Besides tremendous beneficial effects of statins, various forms of muscular toxicity (myalgia, cramp, exercise intolerance, and fatigability) occur frequently. We hypothesized that the iatrogenic effects of statins could result from alterations in Ca(2+) homeostasis. Acute applications of simvastatin on human skeletal muscle fibers triggered a Ca(2+) wave of intra-cellular Ca(2+) that mostly originates from sarcoplasmic reticulum (SR) Ca(2+)-release. In addition, simvastatin increased mitochondrial NADH content and induced mitochondrial membrane depolarization (EC(50)=1.96 microM) suggesting an altered mitochondrial function. Consequently on simvastatin application, a weak mitochondrial Ca(2+) efflux (EC(50)=7.8 microM) through permeability transient pore and Na(+)/Ca(2+) exchanger was triggered, preceding the large SR-Ca(2+) release. Increased SR Ca(2+) content after acute application of statin is also suggested by the increased Ca(2+) spark amplitude and by the effect of cyclopiazonic acid. We thus conclude that simvastatin induced alterations in mitochondrial function which lead to an increase in cytoplasmic Ca(2+), SR-Ca(2+) overload, and Ca(2+) waves. Taken together, these statin-induced muscle dysregulations may contribute to myotoxicity.

Calcium↗

PubMed2005

Relationship between blood lactate concentration and substrate utilization during exercise in type 2 diabetic postmenopausal women.

Increased blood lactate concentration and alterations of substrate utilization have been shown to be partly involved in development of insulin resistance in obese and type 2 diabetic patients. As blood represents the first great distribution space and participates to lactate exchange in whole body, we investigated lactate transport in red blood cells at rest and the potential relationships between elevated blood lactate and substrate utilization in 7 obese controls and 7 obese type 2 diabetic postmenopausal women during an incremental exercise test. Blood samples were collected at rest, 30%, 50%, and 60% of maximal power and at 8 and 20 minutes of recovery time. Baseline lactatemia and its increase during exercise were higher in the diabetic group (P < .05). We found a negative correlation between basal and 30% maximal power lactatemia and 2 indexes of substrate utilization (crossover point: r = -0.79, r = -0.82 and maximal lipid oxidation point: r = -0.83, r = -0.80; P < .05) in diabetic group only. Furthermore, there were positive correlations between the affinity constant, maximal velocity transport, and basal lactate level in diabetic subjects (r = 0.91 and r = 0.73, respectively; P < .05). These results show that the elevation of blood lactate is associated with a greater carbohydrate oxidation in type 2 diabetes, but the mechanisms underlying the alteration of substrate utilization need to be clarified. Furthermore, increased lactate levels cannot be explained by alterations of lactate transport in red blood cells, but it could affect monocarboxylate transporter 1 properties.

Diabetes Mellitus, Type 2↗

PubMed2004

Training effect on performance, substrate balance and blood lactate concentration at maximal lactate steady state in master endurance-runners.

Training effects on time-to-exhaustion, substrate and blood lactate balances at the maximal lactate steady state velocity (MLSSv) were examined. Eleven male, veteran, long-distance runners performed three tests before and after 6 weeks of training at MLSSv: an incremental test to determine maximum O2 uptake (VO(2,max)) and the velocity at the lactate threshold (vLT), a sub-maximal test of two stages of 20 min at 95 and 105% of vLT separated by 40 min rest to determine the MLSSv and the corresponding lactate concentration (MLSSc) and a time-to-exhaustion run at MLSSv for which the substrate balance was calculated. Duration and distance run at MLSSv increased dramatically respectively from 44+/-10 to 63+/-12 min and from 10.4 to 15.7 km respectively (P<0.01). MLSSv increased significantly with training but the relative fraction of VO(2,max) remained the same (85.2+/-4.5 vs. 85.3+/-5.2%, P=0.93). MLSSc was unaffected by training as determined from the percentage of energy yielded by carbohydrates (80%) during the exhaustive run at MLSSv. These findings show that training at MLSS elicits small increases in MLSSv and VO(2,max), but enhances time-to-exhaustion (endurance) at MLSSv substantially (+50%). Training does not change the proportion of carbohydrate oxidized, which is the major substrate used during an exhaustive run at MLSS lasting 1 h.

Adult↗

PubMed2003

The concept of maximal lactate steady state: a bridge between biochemistry, physiology and sport science.

The maximal lactate steady state (MLSS) is defined as the highest blood lactate concentration (MLSSc) and work load (MLSSw) that can be maintained over time without a continual blood lactate accumulation. A close relationship between endurance sport performance and MLSSw has been reported and the average velocity over a marathon is just below MLSSw. This work rate delineates the low- to high-intensity exercises at which carbohydrates contribute more than 50% of the total energy need and at which the fuel mix switches (crosses over) from predominantly fat to predominantly carbohydrate. The rate of metabolic adenosine triphosphate (ATP) turnover increases as a direct function of metabolic power output and the blood lactate at MLSS represents the highest point in the equilibrium between lactate appearance and disappearance both being equal to the lactate turnover. However, MLSSc has been reported to demonstrate a great variability between individuals (from 2-8 mmol/L) in capillary blood and not to be related to MLSSw. The fate of enhanced lactate clearance in trained individuals has been attributed primarily to oxidation in active muscle and gluconeogenesis in liver. The transport of lactate into and out of the cells is facilitated by monocarboxylate transporters (MCTs) which are transmembrane proteins and which are significantly improved by training. Endurance training increases the expression of MCT1 with intervariable effects on MCT4. The relationship between the concentration of the two MCTs and the performance parameters (i.e. the maximal distance run in 20 minutes) in elite athletes has not yet been reported. However, lactate exchange and removal indirectly estimated with velocity constants of the individual blood lactate recovery has been reported to be related to time to exhaustion at maximal oxygen uptake.

Adaptation, Physiological↗