Effect of Long Acting Β2-AGONISTS on Gross Morphology of Skeletal Muscles and Creatine Phosphokinase Level in Simvastatin Induced Myopathies in Rats (original) (raw)
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Preventive Effect of Long Acting Β2-AGONISTS on Statin Induced Myopathies
2018
Objective: To identify the histological effectsof statin-induced skeletal muscle myopathy in a Rat model and tofind protective effect of long acting β2-agonists.Study Design: Laboratory based experimental randomized controlled trial.Place and Duration of Study: Study was conducted at the department of Anatomy, Army Medical CollegeRawalpindi in collaboration with National Institute of Health (NIH) Islamabad and Armed forces institute ofPathology (AFIP) Rawalpindi, from Jan 2015 to Jun 2016.Material and Methods: Adult male Sprague-Dawley rats were procured from NIH Islamabad. Their averageapproximate age was 70-80 days and weight range was 250 ± 50 grams. The animals were randomly selected anddivided into three groups. Group A was the control. Each rat of group B received Simvastatin dissolved indistilled water, by oral gavage (60mg/kg/day) once daily, for 12 weeks. Animals of group C received simvastatindissolved in distilled water, (60mg/kg/day) once daily plus formoterol dissolved ...
Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle
Biochemical Pharmacology, 2011
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Effect of L-carnitine on the skeletal muscle contractility in simvastatin-induced myopathy in rats
Journal of Basic and Clinical Physiology and Pharmacology, 2018
Background Statins therapy is effective in the prevention of cardiovascular events. However, its use is associated with skeletal muscle myopathy, which may be severe enough to discontinue statin therapy, thus exposing patients to more morbidity and mortality. This study was conducted to assess the effect of L-carnitine on the skeletal muscle contractility in a rat model of statin-induced myopathy and to clarify its possible mechanisms. Methods Twenty-one female Sprague Dawley rats were used throughout this study. The rats were divided into the normal control group, statin-induced myopathy group and statin/L-carnitine-treated group. The assessment of gastrocnemius muscle contractility, plasma creatine kinase (CK) levels and oxidative stress markers (malondialdehyde, reduced glutathione) was also carried out done. Results The results of the current study suggest that simvastatin decreased the skeletal muscle mass and altered the muscle contractile properties. It also significantly inc...
Fluvastatin-induced alterations of skeletal muscle function in hypercholesterolaemic rats
Journal of Muscle Research and Cell Motility, 2011
Although statins, the most widely used drugs in the treatment of hyperlipidaemia, are generally accepted as efficient and safe drugs their side-effects on skeletal muscle have been reported with increasing frequency in the past years. The lack of an appropriate animal model in which these side effects would consistently be observed is one of the most important drawbacks in studying statin associated myopathy. To overcome this and enable the studying of the effects of fluvastatin on skeletal muscles an animal model with high blood cholesterol levels was developed. In these animals cholesterol levels rose more than seven fold (from 1.5±0.1 to 10.7±2.0 mmol/L; n=15 and 16) with a dramatic increase in LDL/HDL ratio (from 0.29±0.02 to 1.56±0.17). While the latter was reversed by statin treatment, an elevation in blood creatine kinase level indicated the presence of muscle wasting. Fibers from m. extensor digitorum longus (EDL) showed significant reduction in cross sectional area in the statin treated groups. Statin treatment also decreased the proliferation and fusion of skeletal myotubes in culture. In line with this, resting intracellular calcium concentration ([Ca 2+ ] i) was reduced in statin treated satellite cells and myotubes. On the other hand, in adult skeletal muscle fibers statin treatment increased resting [Ca 2+ ] i (116±4 vs. 151±5 nM; n= 33 and 34) and decreased both twitch and tetanic force both in EDL and m. soleus. In addition, in m. soleus the duration of twitch and tetanic force was shortened. These results clearly indicate that statin administration in these animals results in a myopathy characterized by decreased muscle force and elevated plasma creatine kinase level.
Effect of Statins on Skeletal Muscle Function
Circulation, 2013
H ydroxy-methyl-glutaryl CoA reductase inhibitors or statins are the most effective medications for reducing elevated concentrations of low-density lipoprotein (LDL) cholesterol and produce remarkable reductions in cardiovascular events. 1 Statins can produce life-threatening rhabdomyolysis, but this is rare. 2 Statins are more frequently associated with mild muscle complaints, including myalgia, cramps, and weakness, which may compromise medication compliance and quality of life. The reported incidence of myalgia during statin therapy ranges from 1% in controlled studies 3 to 25% in clinical reports. 4 Muscle weakness has also been reported with statin therapy, but muscle performance and exercise performance have not been carefully studied. 5 Clinical Perspective on p 103 The Effect of Statins on Muscle Performance study (STOMP; National Heart, Lung, and Blood Institute 5R01HL081893, NCT00609063) determined the incidence of statin-associated muscle complaints and examined the effect of statins on muscle performance and exercise capacity by administering atorvastatin 80 mg daily or placebo to healthy subjects for 6 months or until subjects developed myalgia. Methods Study Overview STOMP was a double-blind, random-assignment clinical trial; the methods used have been described previously. 6 Equal numbers of men and women across 3 age ranges (20-39, 40-54, and ≥55 years) were recruited over 4 years. Baseline lipid, liver, kidney, thyroid, and creatine kinase (CK) measurements were obtained. Subjects completed a baseline muscle symptom questionnaire and exercise testing, including a maximal exercise test with gas analysis; hand grip, elbow flexor, and knee extensor strength testing; and a knee extensor endurance exercise test. Subjects were then randomly assigned in a double-blind fashion to identical placebo or atorvastatin 80 mg daily (Lipitor; Pfizer, Inc, New York, NY). Atorvastatin tablets were crushed for compounding, but this does not influence relative bioavailability of the statin (Medical Information Letter 337882; Pfizer, Inc) Subjects were called twice monthly to ascertain symptoms. Subjects performed repeat testing after 6 months or after they developed muscle symptoms meeting the study definition of statin-induced myalgia. The study was approved by the Institutional Review boards at Hartford Hospital, the University of Massachusetts, Background-Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials, and the effect of statins on muscle performance has not been carefully studied. Methods and Results-The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase, exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo was administered for 6 months to 420 healthy, statin-naive subjects. No individual creatine kinase value exceeded 10 times normal, but average creatine kinase increased 20.8±141.1 U/L (P<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 versus 10; P=0.05). Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69). Conclusions-These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in creatine kinase should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance.
Statin-Induced Myopathy: Translational Studies from Preclinical to Clinical Evidence
International Journal of Molecular Sciences, 2021
Statins are the most prescribed and effective drugs to treat cardiovascular diseases (CVD). Nevertheless, these drugs can be responsible for skeletal muscle toxicity which leads to reduced compliance. The discontinuation of therapy increases the incidence of CVD. Thus, it is essential to assess the risk. In fact, many studies have been performed at preclinical and clinical level to investigate pathophysiological mechanisms and clinical implications of statin myotoxicity. Consequently, new toxicological aspects and new biomarkers have arisen. Indeed, these drugs may affect gene transcription and ion transport and contribute to muscle function impairment. Identifying a marker of toxicity is important to prevent or to cure statin induced myopathy while assuring the right therapy for hypercholesterolemia and counteracting CVD. In this review we focused on the mechanisms of muscle damage discovered in preclinical and clinical studies and highlighted the pathological situations in which s...
Frontiers in Pharmacology
Statin therapy may induce skeletal muscle damage ranging from myalgia to severe rhabdomyolysis. Our previous preclinical studies showed that statin treatment in rats involves the reduction of skeletal muscle ClC-1 chloride channel expression and related chloride conductance (gCl). An increase of the activity of protein kinase C theta (PKC theta) isoform, able to inactivate ClC-1, may contribute to destabilize sarcolemma excitability. These effects can be detrimental for muscle function leading to druginduced myopathy. Our goal is to study the causes of statin-induced muscle side effects in patients at the aim to identify biological markers useful to prevent and counteract statin-induced muscle damage. We examined 10 patients, who experienced myalgia and hyper-CK-emia after starting statin therapy compared to 9 non-myopathic subjects not using lipid-lowering drugs. Western Blot (WB) analysis showed a 40% reduction of ClC-1 protein and increased expression of phosphorylated PKC in muscle biopsies of statin-treated patients with respect to untreated subjects, independently from their age and statin type. Real-time PCR analysis showed that despite reduction of the protein, the ClC-1 mRNA was not significantly changed, suggesting posttranscriptional modification. The mRNA expression of a series of genes was also evaluated. MuRF-1 was increased in accord with muscle atrophy, MEF-2, calcineurin (CN) and GLUT-4 transporter were reduced, suggesting altered transcription, alteration of glucose homeostasis and energy deficit. Accordingly, the phosphorylated form of AMPK, measured by WB, was increased, suggesting cytoprotective process activation. In parallel, mRNA expression of Notch-1, involved in muscle cell proliferation, was highly expressed in statin-treated patients, indicating active regeneration. Also, PGC-1-alpha and isocitrate-dehydrogenase increased expression together with increased activity of mitochondrial citrate-synthase, measured by spectrophotometric assay, suggests mitochondrial biogenesis. Thus, the reduction of ClC-1 protein and consequent sarcolemma hyperexcitability together with energy deficiency appear to be among the most important alterations to be associated with statin-related risk of myopathy in
High-dose statins and skeletal muscle metabolism in humans: A randomized, controlled trial
Clinical Pharmacology & Therapeutics, 2005
BackgroundMyopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in skeletal muscle, rarely occurs in patients taking statins. This study was designed to assess the effect of high-dose statin treatment on cholesterol and ubiquinone metabolism and mitochondrial function in human skeletal muscle.Myopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in skeletal muscle, rarely occurs in patients taking statins. This study was designed to assess the effect of high-dose statin treatment on cholesterol and ubiquinone metabolism and mitochondrial function in human skeletal muscle.MethodsForty-eight patients with hypercholesterolemia (33 men and 15 women) were randomly assigned to receive 80 mg/d of simvastatin (n = 16), 40 mg/d of atorvastatin (n = 16), or placebo (n = 16) for 8 weeks. Plasma samples and muscle biopsy specimens were obtained at baseline and at the end of the follow-up.Forty-eight patients with hypercholesterolemia (33 men and 15 women) were randomly assigned to receive 80 mg/d of simvastatin (n = 16), 40 mg/d of atorvastatin (n = 16), or placebo (n = 16) for 8 weeks. Plasma samples and muscle biopsy specimens were obtained at baseline and at the end of the follow-up.ResultsThe ratio of plasma lathosterol to cholesterol, a marker of endogenous cholesterol synthesis, decreased significantly by 66% in both statin groups. Muscle campesterol concentrations increased from 21.1 ± 7.1 nmol/g to 41.2 ± 27.0 nmol/g in the simvastatin group and from 22.6 ± 8.6 nmol/g to 40.0 ± 18.7 nmol/g in the atorvastatin group (P = .005, repeated-measurements ANOVA). The muscle ubiquinone concentration was reduced significantly from 39.7 ± 13.6 nmol/g to 26.4 ± 7.9 nmol/g (P = .031, repeated-measurements ANOVA) in the simvastatin group, but no reduction was observed in the atorvastatin or placebo group. Respiratory chain enzyme activities were assessed in 6 patients taking simvastatin with markedly reduced muscle ubiquinone and in matched subjects selected from the atorvastatin (n = 6) and placebo (n = 6) groups. Respiratory chain enzyme and citrate synthase activities were reduced in the patients taking simvastatin.The ratio of plasma lathosterol to cholesterol, a marker of endogenous cholesterol synthesis, decreased significantly by 66% in both statin groups. Muscle campesterol concentrations increased from 21.1 ± 7.1 nmol/g to 41.2 ± 27.0 nmol/g in the simvastatin group and from 22.6 ± 8.6 nmol/g to 40.0 ± 18.7 nmol/g in the atorvastatin group (P = .005, repeated-measurements ANOVA). The muscle ubiquinone concentration was reduced significantly from 39.7 ± 13.6 nmol/g to 26.4 ± 7.9 nmol/g (P = .031, repeated-measurements ANOVA) in the simvastatin group, but no reduction was observed in the atorvastatin or placebo group. Respiratory chain enzyme activities were assessed in 6 patients taking simvastatin with markedly reduced muscle ubiquinone and in matched subjects selected from the atorvastatin (n = 6) and placebo (n = 6) groups. Respiratory chain enzyme and citrate synthase activities were reduced in the patients taking simvastatin.ConclusionsHigh-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.Clinical Pharmacology & Therapeutics (2005) 78, 60–68; doi: 10.1016/j.clpt.2005.03.006High-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.Clinical Pharmacology & Therapeutics (2005) 78, 60–68; doi: 10.1016/j.clpt.2005.03.006