Laurence Rasseneur

Atorvastatin treatment reduces exercise capacities in rats: involvement of mitochondrial impairments and oxidative stress

Physical exercise exacerbates the cytotoxic effects of statins in skeletal muscle. Mitochondrial impairments may play an important role in the development of muscular symptoms following statin treatment. Our objective was to characterize mitochondrial function and reactive oxygen species (ROS) production in skeletal muscle after exhaustive exercise in atorvastatin-treated rats. The animals were divided into four groups: resting control (CONT; n = 8) and exercise rats (CONT+EXE; n = 8) as well as resting (ATO; n = 10) and exercise (ATO+EXE; n = 8) rats that were treated with atorvastatin (10 mg·kg(-1)·day(-1) for 2 wk). Exhaustive exercise showed that the distance that was covered by treated animals was reduced (P < 0.05). Using dihydroethidium staining, we showed that the ROS level was increased by 60% in the plantaris muscle of ATO compared with CONT rats and was highly increased in ATO+EXE (226%) compared with that in CONT+EXE rats. The maximal mitochondrial respiration (V(max)) was decreased in ATO rats compared with that in CONT rats (P < 0.01). In CONT+EXE rats, V(max) significantly increased compared with those in CONT rats (P < 0.05). V(max) was significantly lower in ATO+EXE rats (-39%) compared with that in CONT+EXE rats (P < 0.001). The distance that was covered by rats significantly correlated with V(max) (r = 0.62, P < 0.01). The glycogen content was decreased in ATO, CONT+EXE, and ATO+EXE rats compared with that in CONT rats (P < 0.05). GLUT-4 mRNA expression was higher after exhaustive exercise in CONT+EXE rats compared with the other groups (P < 0.05). Our results show that exhaustive exercise exacerbated metabolic perturbations and ROS production in skeletal muscle, which may reduce the exercise capacity and promote the muscular symptoms in sedentary atorvastatin-treated animals.

Different timing of changes in mitochondrial functions following endurance training.

PURPOSE The objective of this study was to investigate the time course of the endurance training-induced adaptations in two major mitochondrial functions. METHODS Forty rats were divided into four groups: a control group and three training groups--a 1-d training group, a 5-d training group, and a 10-d training group. The training protocol consisted of 30 min of running on a motorized treadmill (26 m·min(-1), 15% grade). Nuclear respiratory factor-1; transcription factor A, mitochondrial; superoxide dismutase-2; glutathione peroxidase-4; and citrate synthase (CS) messenger RNA levels were measured by qPCR. Mitochondrial respiration and H2O2 release were assessed using permeabilized fibers of white gastrocnemius in situ. Calculation of free radical leak was performed in two conditions where substrates were identical in both measurements. CS activity was assessed spectrophotometrically. RESULTS An early time-dependent modulation in messenger RNA levels was observed with training: nuclear respiratory factor-1 and superoxide dismutase-2 levels increased after acute exercise, transcription factor A, mitochondrial and CS levels improved after 5 d, and glutathione peroxidase-4 levels increased after 10 d. CS activity improved by 29% ± 8% (P < 0.01) after 5 d together with a 50% ± 7% reduction in the free radical leak (P < 0.05). Finally, 10 d of endurance training did not significantly alter mitochondrial H2O2 release but increased mitochondrial respiration rates in situ (P < 0.05). CONCLUSIONS Our results demonstrate that mitochondrial adaptations follow a sequential program in which mitochondrial respiration and free radical leak adaptations occur according to a different timing. Collectively, these results suggest early mitochondrial qualitative adaptations in response to endurance training.

Mitochondria of trained skeletal muscle are protected from deleterious effects of statins

Introduction: Statins are associated with adverse skeletal muscle effects. Our objective was to determine if muscular adaptations following exercise training prevented deleterious effects of atorvastatin in glycolytic skeletal muscle. Methods: Twenty rats were divided into 2 groups: a control group (n = 10; Cont) and a 10 days of training group (n = 10; Training). Using the permeabilized fibers technique, we explored mitochondrial function. Results: Exercise training increased Vmax and H2O2 production without altering the free radical leak, and mRNA expression of SOD2 and Cox1 were higher in trained muscle. In the Cont group, atorvastatin exposure increased H2O2 production and decreased skeletal muscle Vmax. The decreased Vmax effect of atorvastatin was dose dependent. Interestingly, the half‐maximal inhibitory concentration (IC50) was higher in the Training group. H2O2 production increased in trained muscle after atorvastatin exposure. Conclusions: These results suggest that improvements in mitochondrial respiratory and antioxidant capacities following endurance training protected mitochondria against statin exposure. Muscle Nerve 46: 367–373, 2012

Effect of angiotensin‐converting enzyme inhibition on skeletal muscle oxidative function and exercise capacity in streptozotocin‐induced diabetic rats

Since exercise capacity is related to the mitochondrial respiration rate in skeletal muscle and both parameters are potentially modulated by the onset of diabetes and by inhibition of the angiotensin‐converting enzyme (ACE), we investigated whether skeletal muscle oxidative functions and exercise capacities are impaired in chronic streptozotocin‐induced diabetic (STZ) rats and whether ACE inhibition could reverse such abnormalities. The ACE inhibitor perindopril (2 mg kg−1 day−1) was given for a period of 5 weeks to 7‐month‐old STZ rats (DIA‐PE, n= 8) whose haemodynamic function, skeletal muscle mitochondrial function and exercise capacity were compared with those of untreated diabetic (DIA, n= 8) and control rats (CONT, n= 8). Increased arterial blood pressure (157 ± 12 versus 130 ± 6 mmHg, P < 0.05) and reduced exercise capacity (29 ± 2 versus 91 ± 2 min, respectively, P < 0.01) were observed in DIA compared with CONT. The oxidative capacity of the gastrocnemius muscle was significantly reduced in DIA compared with CONT rats (5.4 ± 0.5 versus 10.6 ± 0.7 μmol O2 min−1(g dry weight)−1, respectively, P < 0.001). Moreover, the coupling between oxidation and phosphorylation was significantly impaired in DIA (−52%, P < 0.001). Angiotensin‐converting enzyme inhibition (ACEi) normalized blood pressure without improving mitochondrial function (4.3 ± 0.8 μmol O2 min−1 (g dry weight)−1 in DIA‐PE rats) but reduced exercise capacity to even lower levels (10 ± 1 min, P < 0.01). Exercise capacity correlated positively with blood pressure in DIA‐PE (r= 0.79, P < 0.05). In experimental type 1 diabetic rats, both skeletal muscle mitochondrial respiration and exercise capacity are impaired. The ACEi failed to restore the muscular function and worsened exercise capacity. Further studies will be useful to determine whether an inadequate muscular blood flow secondary to the reduction in mean systemic blood pressure can explain these results.

Effect of eccentric versus concentric exercise training on mitochondrial function

Introduction: The effect of eccentric (ECC) versus concentric (CON) training on metabolic properties in skeletal muscle is understood poorly. We determined the responses in oxidative capacity and mitochondrial H2O2 production after eccentric (ECC) versus concentric (CON) training performed at similar mechanical power. Methods: Forty‐eight rats performed 5‐ or 20‐day eccentric (ECC) or concentric (CON) training programs. Mitochondrial respiration, H2O2 production, citrate synthase activity (CS), and skeletal muscle damage were assessed in gastrocnemius (GAS), soleus (SOL) and vastus intermedius (VI) muscles. Results: Maximal mitochondrial respiration improved only after 20 days of concentric (CON) training in GAS and SOL. H2O2 production increased specifically after 20 days of eccentric ECC training in VI. Skeletal muscle damage occurred transiently in VI after 5 days of ECC training. Conclusions: Twenty days of ECC versus CON training performed at similar mechanical power output do not increase skeletal muscle oxidative capacities, but it elevates mitochondrial H2O2 production in VI, presumably linked to transient muscle damage. Muscle Nerve 50: 803–811, 2014

Mitochondrial function following downhill and/or uphill exercise training in rats.

Introduction: The goal of this study was to compare the effects of downhill (DH), uphill (UH), and UH‐DH exercise training, at the same metabolic rate, on exercise capacity and skeletal muscle mitochondrial function. Methods: Thirty‐two Wistar rats were separated into a control and 3 trained groups. The trained groups exercised for 4 weeks, 5 times per week at the same metabolic rate, either in UH, DH, or combined UH‐DH. Twenty‐four hours after the last training session, the soleus, gastrocnemius, and vastus intermedius muscles were removed for assessment of mitochondrial respiration. Results: Exercise training, at the same metabolic rate, improved maximal running speed without specificity for exercise modalities. Maximal fiber respiration was enhanced in soleus and vastus intermedius in the UH group only. Conclusions: Exercise training, performed at the same metabolic rate, improved exercise capacity, but only UH‐trained rats enhanced mitochondrial function in both soleus and vastus intermedius skeletal muscle. Muscle Nerve 54: 925–935, 2016

P173 Effets d’un entraînement en endurance sur les capacités à l’exercice et la fonction mitochondriale de rats diabétiques de type 1

Objectif Evaluer l’impact d’un entrainement en endurance de 10 semaines sur les capacites a l’exercice et la fonction mitochondriale de rats diabetiques de type 1. Materiels et Methodes Trente cinq rats mâles Wistar ont ete randomises dans quatre groupes : 6 temoins sedentaires, 7 temoins entraines, 11 diabetiques sedentaires et 11 diabetiques entraines. A dix sept semaines d’âge, le diabete a ete induit par injection intraveineuse de 65 mg/kg de streptozotocine. L’entrainement a ete realise sur un tapis roulant (pente a 10°), 5 jours par semaine, durant 10 semaines a une vitesse de 25 cm. s−1. La duree d’entrainement initiale de 10 minutes a ete progressivement augmentee jusqu’a 50 minutes. La fonction mitochondriale a ete evaluee par l’etude ex vivo de la respiration mitochondriale sur fibres permeabilisees du muscle gastrocnemien superficiel (glycolytique) et du muscle soleaire (oxydatif). Les capacites a l’exercice ont ete evaluees par un test de vitesse maximale toleree ou la vitesse de course (pente a 10°) etait incrementee de 5 cm. s−1 toutes les 2 minutes jusqu’a epuisement. Resultats Les rats diabetiques sedentaires ont une vitesse maximale toleree significativement diminuee (25,1 ± 2,3 cm. s−1) et une dysfonction mitochondriale des muscles soleaire (7,75 ± 0,42 μM/min/g poids sec) et gastrocnemien (4,88 ± 0,47 μM/min/g poids sec). L’entrainement a permis d’augmenter la vitesse maximale toleree des rats diabetiques (50,6 ± 1,3 cm. s−1) a un niveau comparable aux rats temoins entraine et de preserver la fonction mitochondriale du muscle soleaire (10,42 ± 0,58 μM/min/g poids sec), sans effet pour le muscle gastrocnemien (5,73 ± 0,48 μM/min/g poids sec). Conclusion L’entrainement preserve la fonction mitochondriale des muscles oxydatifs, ce qui se traduit par des capacites a l’exercice maintenue a un niveau comparable a celui de rats temoins.