Exercise Training Protects against Atorvastatin-Induced Skeletal Muscle Dysfunction and Mitochondrial Dysfunction in the Skeletal Muscle of Rats.
ABSTRACT: Statins are used to prevent and treat atherosclerotic cardiovascular disease, but they also induce myopathy and mitochondrial dysfunction. Here, we investigated whether exercise training prevents glucose intolerance, muscle impairment, and mitochondrial dysfunction in the skeletal muscles of Wistar rats treated with atorvastatin (5 mg kg-1 day-1) for 12 weeks. The rats were assigned to the following three groups: the control (CON), atorvastatin-treated (ATO), and ATO plus aerobic exercise training groups (ATO+EXE). The ATO+EXE group exhibited higher glucose tolerance and forelimb strength and lower creatine kinase levels than the other groups. Mitochondrial respiratory and Ca2+ retention capacity was significantly lower in the ATO group than in the other groups, but exercise training protected against atorvastatin-induced impairment in both the soleus and white gastrocnemius muscles. The mitochondrial H2O2 emission rate was relatively higher in the ATO group and lower in the ATO+EXE group, in both the soleus and white gastrocnemius muscles, than in the CON group. In the soleus muscle, the Bcl-2, SOD1, SOD2, Akt, and AMPK phosphorylation levels were significantly higher in the ATO+EXE group than in the ATO group. In the white gastrocnemius muscle, the SOD2, Akt, and AMPK phosphorylation levels were significantly higher in the ATO+EXE group than in the ATO group. Therefore, exercise training might regulate atorvastatin-induced muscle damage, muscle fatigue, and mitochondrial dysfunction in the skeletal muscles.
Project description:AIMS:To investigate differential muscle atrophy during bed-rest, the impact of a high-intensity concentric-eccentric (flywheel) resistance exercise countermeasure and muscle recovery after bed-rest. METHODS:Twenty-five healthy male subjects underwent 90 dayshead-down tilt bed-rest. Volume of individual lower-limb muscles was measured via MRI before, twice during and four times up to 1 year after bed-rest. Subjects were either inactive (n=16) or performed flywheel exercise every third day of bed-rest (n=9). Functional performance was assessed via countermovement jump. RESULTS:On 'intent-to-treat' analysis, flywheel prevented atrophy in the vasti (p<0.001) and reduced atrophy in the hip adductor/extensor adductor magnus (p=0.001) and ankle dorsiflexors/toe flexors (soleus (p<0.001), gastrocnemius medialis (p<0.001), gastrocnemius lateralis (p=0.02), and tibialis posterior with flexor digitorum longus (p=0.04)). Flywheel exercise was not effective for the hamstrings, gracilis, sartorius, peroneals and anterior tibial muscles. Muscle atrophy in vasti, soleus, gastrocnemius medialis, gastrocnemius lateralis and adductor magnus correlated with losses in countermovement jump performance. Muscle volume recovered within 90 days after bed-rest, however long-term after bed-rest, the inactive subjects only showed significantly increased muscle volume versus prebed-rest in a number of muscles including soleus (+4.3%), gastrocnemius medialis (+3.9%) and semimembranosus (+4.3%). This was not associated with greater countermovement jump performance. CONCLUSION:The exercise countermeasure was effective in preventing or reducing atrophy in the vasti, adductor magnus and ankle dorsiflexors/toe flexors but not the hamstrings, medial thigh muscles or peroneals and dorsiflexor muscles. TRIAL REGISTRATION NUMBER:NCT00311571; results.
Project description:Mammalian skeletal muscles exhibit age-related adaptive and pathological remodeling. Several muscles in particular undergo progressive atrophy and degeneration beyond median lifespan. To better understand myocellular responses to aging, we used semi-quantitative global metabolomic profiling to characterize trends in metabolic changes between 15-month-old adult and 32-month-old aged Fischer 344 × Brown Norway (FBN) male rats. The FBN rat gastrocnemius muscle exhibits age-dependent atrophy, whereas the soleus muscle, up until 32 months, exhibits markedly fewer signs of atrophy. Both gastrocnemius and soleus muscles were analyzed, as well as plasma and urine. Compared to adult gastrocnemius, aged gastrocnemius showed evidence of reduced glycolytic metabolism, including accumulation of glycolytic, glycogenolytic, and pentose phosphate pathway intermediates. Pyruvate was elevated with age, yet levels of citrate and nicotinamide adenine dinucleotide were reduced, consistent with mitochondrial abnormalities. Indicative of muscle atrophy, 3-methylhistidine and free amino acids were elevated in aged gastrocnemius. The monounsaturated fatty acids oleate, cis-vaccenate, and palmitoleate also increased in aged gastrocnemius, suggesting altered lipid metabolism. Compared to gastrocnemius, aged soleus exhibited far fewer changes in carbohydrate metabolism, but did show reductions in several glycolytic intermediates, fumarate, malate, and flavin adenine dinucleotide. Plasma biochemicals showing the largest age-related increases included glycocholate, heme, 1,5-anhydroglucitol, 1-palmitoleoyl-glycerophosphocholine, palmitoleate, and creatine. These changes suggest reduced insulin sensitivity in aged FBN rats. Altogether, these data highlight skeletal muscle group-specific perturbations of glucose and lipid metabolism consistent with mitochondrial dysfunction in aged FBN rats.
Project description:<h4>Background</h4>Although exercise is often prescribed for the management of cardiovascular diseases, a non-invasive imaging approach that quantifies skeletal muscle physiology and correlates with patients' functional capacity and cardiovascular fitness has been absent. Therefore, we evaluated the potential of lower extremity single photon emission computed tomography (SPECT)/CT perfusion imaging as a non-invasive correlate to exercise tolerance and cardiovascular fitness.<h4>Methods</h4>Patients (n?=?31) undergoing SPECT/CT myocardial perfusion imaging underwent additional stress/rest SPECT/CT imaging of the lower extremities. CT-based image segmentation was used for regional quantification of perfusion reserve within the tibialis anterior, soleus, and gastrocnemius muscles. Metabolic equivalents (METs) at peak exercise and heart rate recovery (HRR) after exercise were recorded.<h4>Results</h4>Peak METs were significantly associated with perfusion reserve of tibialis anterior (p?=?0.02), soleus (p?=?0.01) and gastrocnemius (p?=?0.01). HRR was significantly associated with perfusion reserve of the soleus (p?=?0.02) and gastrocnemius (p?=?0.04) muscles. Perfusion reserve of the tibialis anterior (40.6?±?20.2%), soleus (35.4?±?16.7%), and gastrocnemius (29.7?±?19.1%) all significantly differed from each other.<h4>Conclusions</h4>SPECT/CT imaging provides regional quantification of skeletal muscle perfusion reserve which is significantly associated with exercise tolerance and cardiovascular fitness. Future application of SPECT/CT may elucidate the underlying skeletal muscle adapations to exercise therapy in patients with cardiovascular diseases.
Project description:<h4>Aim</h4>Exercise is able to increase both muscle protein synthesis and mitochondrial biogenesis. However, acidosis, which can occur in pathological states as well as during high-intensity exercise, can decrease mitochondrial function, whilst its impact on muscle protein synthesis is disputed. Thus, the aim of this study was to determine the effect of a mild physiological decrease in pH, by administration of ammonium chloride, on myofibrillar and mitochondrial protein synthesis, as well as associated molecular signaling events.<h4>Methods</h4>Male Wistar rats were given either a placebo or ammonium chloride prior to a short interval training session. Rats were killed before exercise, immediately after exercise, or 3 h after exercise.<h4>Results</h4>Myofibrillar (p = 0.036) fractional protein synthesis rates was increased immediately after exercise in the soleus muscle of the placebo group, but this effect was absent in the ammonium chloride group. However, in the gastrocnemius muscle NH<sub>4</sub> Cl increased myofibrillar (p = 0.044) and mitochondrial protein synthesis (0 h after exercise p = 0.01; 3 h after exercise p = 0.003). This was accompanied by some small differences in protein phosphorylation and mRNA expression.<h4>Conclusion</h4>This study found ammonium chloride administration immediately prior to a single session of exercise in rats had differing effects on mitochondrial and myofibrillar protein synthesis rates in soleus (type I) and gastrocnemius (type II) muscle in rats.
Project description:Endurance exercise is a remarkable intervention for the treatment of many diseases. Mitochondrial changes on skeletal muscle are likely important for many of the benefits provided by exercise. In this study, we aimed to evaluate the effects that a regular physical activity (swimming without workload) has on mitochondrial morphological alterations and glucometabolic parameters induced by a high-sugar diet (HSD). Weaned male Wistar rats fed with a standard diet or a HSD (68% carbohydrate) were subjected to 60 minutes of regular physical activity by swimming (without workload) for four- (20 sessions) or eight-week (40 sessions) periods. After training, animals were euthanized and the sera, adipose tissues, and skeletal muscles were collected for further analysis. The HSD increased body weight after an 8-week period; it also increased the fat pads and the adipose index, resulting in glucose intolerance and insulin resistance (IR). Transmission electron microscopy showed an increase in alterations of mitochondrial ultrastructure in the gastrocnemius muscle, as well as a decrease in superoxide dismutase (SOD) activity, and an increase in protein carbonylation. Regular physical activity partially reverted these alterations in rats fed a HSD, preventing mitochondrial morphological alterations and IR. Moreover, we observed a decrease in Pgc1? expression (qPCR analysis) in STD-EXE group and a less pronounced reduction in HSD-EXE group after an 8-week period. Thus, regular physical activity (swimming without workload) in rats fed a HSD can prevent mitochondrial dysfunction and IR, highlighting the crucial role for physical activity on metabolic homeostasis.
Project description:It has been proposed that superior muscle hypertrophy may be obtained by training muscles predominant in type I fibers with lighter loads and those predominant in type II fibers with heavier loads. PURPOSE:To evaluate longitudinal changes in muscle strength and hypertrophy of the soleus (a predominantly slow-twitch muscle) and gastrocnemius (muscle with a similar composition of slow and fast-twitch fibers) when subjected to light (20-30 repetition maximum) and heavy (6-10 repetition maximum) load plantarflexion exercise. METHODS:The study employed a within-subject design whereby 26 untrained young men had their lower limbs randomized to perform plantarflexion with a low-load (LIGHT) and a high-load (HEAVY) for 8 weeks. Muscle thickness was estimated via B-mode ultrasound and maximal strength was determined by isometric dynamometry. RESULTS:Results showed that changes in muscle thickness were similar for the soleus and the gastrocnemius regardless of the magnitude of load used in training. Furthermore, each of the calf muscles demonstrated robust hypertrophy, with the lateral gastrocnemius showing greater gains compared to the medial gastrocnemius and soleus. Both HEAVY and LIGHT training programs elicited similar hypertrophic increases in the triceps surae. Finally, isometric strength increases were similar between loading conditions. CONCLUSIONS:The triceps surae muscles respond robustly to regimented exercise and measures of muscle hypertrophy and isometric strength appear independent of muscle fiber type composition. Moreover, the study provides further evidence that low-load training is a viable strategy to increase hypertrophy in different human muscles, with hypertrophic increases similar to that observed using heavy loads.
Project description:Oxidative capacity of muscles correlates with capillary density and with microcirculation, which in turn depend on various regulatory factors, including NO generated by endothelial nitric oxide synthase (eNOS). To determine the role of eNOS in patterns of regulation of energy metabolism in various muscles, we studied mitochondrial respiration in situ in saponin-permeabilized fibres as well as the energy metabolism enzyme profile in the cardiac, soleus (oxidative) and gastrocnemius (glycolytic) muscles isolated from mice lacking eNOS (eNOS(-/-)). In soleus muscle, the absence of eNOS induced a marked decrease in both basal mitochondrial respiration without ADP (-32%; P <0.05) and maximal respiration in the presence of ADP (-29%; P <0.05). Furthermore, the eNOS(-/-) soleus muscle showed a decrease in total creatine kinase (-29%; P <0.05), citrate synthase (-31%; P <0.01), adenylate kinase (-27%; P <0.05), glyceraldehyde-3-phosphate dehydrogenase (-43%; P <0.01) and pyruvate kinase (-26%; P <0.05) activities. The percentage of myosin heavy chains I (slow isoform) was significantly increased from 24.3+/-1.5% in control to 30.1+/-1.1% in eNOS(-/-) soleus muscle ( P <0.05) at the expense of a slight non-significant decrease in the three other (fast) isoforms. Besides, eNOS(-/-) soleus showed a 28% loss of weight. Interestingly, we did not find differences in any parameters in cardiac and gastrocnemius muscles compared with respective controls. These results show that eNOS knockout has an important effect on muscle oxidative capacity as well on the activities of energy metabolism enzymes in oxidative (soleus) muscle. The absence of such effects in cardiac and glycolytic (gastrocnemius) muscle suggests a specific role for eNOS-produced NO in oxidative skeletal muscle.
Project description:The aim of this study was to determine the role of the phosphorylation state of glycogen synthase and glycogen phosphorylase in the regulation of muscle glycogen repletion in fasted animals recovering from high-intensity exercise. Groups of rats were swum to exhaustion and allowed to recover for up to 120 min without access to food. Swimming to exhaustion caused substantial glycogen breakdown and lactate accumulation in the red, white and mixed gastrocnemius muscles, whereas the glycogen content in the soleus muscle remained stable. During the first 40 min of recovery, significant repletion of glycogen occurred in all muscles examined except the soleus muscle. At the onset of recovery, the activity ratios and fractional velocities of glycogen synthase in the red, white and mixed gastrocnemius muscles were higher than basal, but returned to pre-exercise levels within 20 min after exercise. In contrast, after exercise the activity ratios of glycogen phosphorylase in the same muscles were lower than basal, and increased to pre-exercise levels within 20 min. This pattern of changes in glycogen synthase and phosphorylase activities, never reported before, suggests that the integrated regulation of the phosphorylation state of both glycogen synthase and phosphorylase might be involved in the control of glycogen deposition after high-intensity exercise.
Project description:Nuclear factor (NF)?B is a transcription factor that controls immune and inflammatory signaling pathways. In skeletal muscle, NF?B has been implicated in the regulation of metabolic processes and tissue mass, yet its affects on mitochondrial function in this tissue are unclear. To investigate the role of NF?B on mitochondrial function and its relationship with muscle mass across the life span, we study a mouse model with muscle-specific NF?B suppression (muscle-specific I?B? super-repressor [MISR] mice). In wild-type mice, there was a natural decline in muscle mass with aging that was accompanied by decreased mitochondrial function and mRNA expression of electron transport chain subunits. NF?B inactivation downregulated expression of PPARGC1A, and upregulated TFEB and PPARGC1B. NF?B inactivation also decreased gastrocnemius (but not soleus) muscle mass in early life (1-6 months old). Lower oxygen consumption rates occurred in gastrocnemius and soleus muscles from young MISR mice, whereas soleus (but not gastrocnemius) muscles from old MISR mice displayed increased oxygen consumption compared to age-matched controls. We conclude that the NF?B pathway plays an important role in muscle development and growth. The extent to which NF?B suppression alters mitochondrial function is age dependent and muscle specific. Finally, mitochondrial function and muscle mass are tightly associated in both genotypes and across the life span.
Project description:The present study aimed to investigate the differential response of oxidative (soleus) and glycolytic (gastrocnemius) muscles to heat-induced endoplasmic reticulum (ER) stress. It was hypothesized that due to compositional and functional differences, both muscles respond differently to acute heat stress. To address this, male Sprague Dawley rats (12/group) were subjected to thermoneutral (25 °C) or heat stress (42 °C) conditions for 1 h. Soleus and gastrocnemius muscles were removed for analysis post-exposure. A significant increase in body temperature and free radical generation was observed in both the muscles following heat exposure. This further caused a significant increase in protein carbonyl content, AOPP, and lipid peroxidation in heat-stressed muscles. These changes were more pronounced in heat-stressed soleus compared to the gastrocnemius muscle. Accumulation of unfolded, denatured proteins results in ER stress, causing activation of unfolded protein response (UPR) pathway. The expressions of UPR transducers were significantly higher in soleus as compared to the gastrocnemius muscle. A significant elevation in resting intracellular calcium ion was also observed in heat-stressed soleus muscle. Overloading of cells with misfolded proteins in soleus muscle activated ER-induced apoptosis as indicated by significant upregulation of C/EBP homologous protein and Caspase12. The study provides a detailed mechanistic representation of the differential response of muscles toward UPR under heat stress. Data suggests that soleus majorly being an oxidative muscle is more prone to heat stress-induced insult indicated by enhanced apoptosis. This study may aid in devising mitigation strategies to improve muscle performance under heat stress.