|Year : 2017 | Volume
| Issue : 4 | Page : 1117-1124
Histological study on the effect of rosuvastatin (Crestor) on the skeletal muscle of adult male albino rats and the possible protective effect of coenzyme Q10
Maha E Soliman1, Samy E Atteia1, Maisa A Kefafy1, Amira F Ali1, Eman M Radwan2
1 Department of Histology, Faculty of Medicine, Menoufia University, Menoufia, Helwan, Egypt
2 Department of Histology, Faculty of Medicine, Helwan University, Helwan, Egypt
|Date of Submission||29-Aug-2016|
|Date of Acceptance||11-Dec-2016|
|Date of Web Publication||04-Apr-2018|
Eman M Radwan
Source of Support: None, Conflict of Interest: None
The aim of this study was to evaluate the effect of rosuvastatin drug on the histological structure of the skeletal muscle fiber of adult male albino rats and the possible protective role of coenzyme Q10.
Rosuvastatin has been proven to be effective in improving serum lipid profiles. It decreases the risk for mortality in patients with coronary heart disease. It was reported that some patients treated with various statins have developed symptoms of myopathy. Coenzyme Q10 has a powerful antioxidant activity and affects membrane stability in many tissues, including skeletal muscle.
Materials and methods
A total of 54 adult male albino rats were used in this study and divided into four groups: group I rats served as negative controls, group II rats served as positive controls, group III rats were treated with rosuvastatin orally for 4 and 12 weeks, and group IV rats were treated with rosuvastatin and Coenzyme Q10 orally for 4 and 12 weeks. The gastrocnemius muscle was dissected and prepared for light and electron microscopic study.
The light microscopic study of the gastrocnemius muscle of rats treated with a high therapeutic dose of rosuvastatin for 4 and 12 weeks (group III) showed variation in size, mononuclear cellular infiltration, splitting, and focal degeneration of myofibers with increased collagen fiber deposition between muscle fibers. Electron microscopic study showed mitochondrial accumulation between myofibrils and in the subsarcolemmal space, mitochondrial degeneration, and dilatation of sarcoplasmic reticulum cisterna. Coadministration of coenzyme Q10 with rosuvastatin for 4 and 12 weeks ameliorated most of the above-mentioned histological alterations in the rat skeletal muscles.
Rosuvastatin drug caused skeletal muscle fiber damage. Coenzyme Q10 leads to the protection of the skeletal muscle fibers when given concomitantly with rosuvastatin.
Keywords: albino rats, coenzyme Q10, rosuvastatin, skeletal muscle, statins
|How to cite this article:|
Soliman ME, Atteia SE, Kefafy MA, Ali AF, Radwan EM. Histological study on the effect of rosuvastatin (Crestor) on the skeletal muscle of adult male albino rats and the possible protective effect of coenzyme Q10. Menoufia Med J 2017;30:1117-24
|How to cite this URL:|
Soliman ME, Atteia SE, Kefafy MA, Ali AF, Radwan EM. Histological study on the effect of rosuvastatin (Crestor) on the skeletal muscle of adult male albino rats and the possible protective effect of coenzyme Q10. Menoufia Med J [serial online] 2017 [cited 2018 Jul 21];30:1117-24. Available from: http://www.mmj.eg.net/text.asp?2017/30/4/1117/229223
| Introduction|| |
Atherosclerosis and its complications such as stroke, myocardial infarction, and peripheral vascular diseases remain important causes of morbidity and mortality in industrialized and developing countries. Therefore, it is of utmost importance to develop strategies for preventing and treating atherosclerosis. Statins are a drug family shown to decrease cardiovascular-related mortality and morbidity through the reduction of low-density lipoproteins (LDLs).
By suppressing the key enzyme in cholesterol biosynthesis [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase], statins are used as an effective treatment for hypercholesterolemia. Enzyme inhibition in the liver, the major site of cholesterol biosynthesis, leads to the reduction of plasma cholesterol, causing an increased synthesis of hepatic cell surface membrane LDL receptors. This induces an increased hepatic uptake of plasma LDL with a reduction in circulating levels. Statins have anti-inflammatory and antioxidant potentials, which are independent of their cholesterol-lowering effect, and are termed as pleiotropic effects.
The renal, hepatic, and muscular systems were found to be affected during statin therapy. The skeletal muscles were the most commonly affected ones. This varies from myalagia (muscle pain without elevation of creatine kinase) to myositis (muscle pain or weakness associated with a higher level of creatine kinase) and rhabdomyolysis (an acute degeneration of skeletal muscle with a higher level of creatine kinase and creatinine as well as myoglobinuria).
The exact mechanisms underlying statin-associated myopathy are not well understood; however, theories do exist. Attention has been directed, among other factors, toward the influence of lipophilicity/hydrophilicity of the statin, alterations in intracellular ubiquinone (coenzyme Q10) concentrations, organic anion transporters, and muscle energy metabolism.
Rosuvastatin has been reported to be efficacious in improving serum lipid profiles. Recently published data from the JUPITER study confirmed the effectiveness of this statin in primary prevention for older patients with multiple risk factors and inflammation. Rosuvastatin exhibits high hepatoselectivity and hydrophilicity and low systemic bioavailability while undergoing minimal metabolism through the cytochrome P450 system. Therefore, rosuvastatin has an interesting pharmacokinetic profile that is different from that of other statins. However, it is yet to be established whether this might translate into a better safety profile. Herein, we review evidence with regard to the safety of this statin on skeletal muscles.
Coenzyme Q10, a natural antioxidant, is widely distributed throughout the human body. It is a lipid-soluble provitamin that is structurally similar to vitamin K. It is incorporated into the walls of mitochondria and functions in electron transport and the production of the high-energy compound ATP. Because of its lipid solubility, it is present in the cell membrane phospholipid layer and may induce membrane stability as well. Its concentration is highest in tissues with high-energy needs, such as cardiac muscle, skeletal muscle, and kidney and liver tissues. It is well located in membranes in close relation to the unsaturated lipid chains to act as a primary scavenger of free radicals.
Many research studies have focused on the role of coenzyme Q10 deficiency in the development of statin myopathy. Although it is present in a wide variety of foods, coenzyme Q10 is mainly supplied by means of in-vivo biosynthesis, a process that involves the enzyme HMG-CoA reductase, which is also responsible for cholesterol synthesis. Coenzyme Q10 synthesis appears to be stimulated in the rough endoplasmic reticulum and the final condensation reaction occurs in the Golgi apparatus. HMG-CoA reductase inhibitors (statins) have been proven to decrease the levels of coenzyme Q10 in a dose-dependent manner, which could be corrected through coadministration with coenzyme Q10.
| Aim|| |
The aim of the present work was to study the histological changes that occur in the skeletal muscle of the adult male albino rats during the administration of rosuvastatin and to clarify the possible protective effect of coenzyme Q10.
| Materials and Methods|| |
The study was approved from the ethical committees of faculty of medicine Menoufia University. It included 54 male albino rats weighing 100–150 g. They were housed in hygienic stainless steel cages and kept in clean well-ventilated room. They were allowed free access to water and fed ad libitum. Strict care and hygiene were taken to maintain normal and healthy environment for all rats all time. The general conditions and behavior of the animals were noticed. The dose of rosuvastatin was 0.5 mg/day/animal, which was equivalent to the high human therapeutic dose (40 mg daily). The dose of coenzyme Q10 was 3 mg/day/animal, which was equivalent to 200 mg/day for humans. Both drugs were administrated orally using a gastric tube.
The animals were divided into four main groups.
Group I (negative control) comprised 18 rats; six rats received no treatment, six rats received 2 ml of water containing 0.5% hydroxypropyl methylcellulose (so for rosuvastatin), and six rats received soybean oil (solvent for coenzyme Q10) through oral route for 12 weeks.
Group II (coenzyme Q10-treated) comprised 12 rats. Each rat received coenzyme Q10 at a dose of 3 mg/day/animal dissolved in soybean oil through oral route for 12 weeks.
Group III (rosuvastatin-treated) comprised 12 rats. Each rat received rosuvastatin at a dose of 0.5 mg/day/animal suspended in water containing 0.5% hydroxypropyl methylcellulose through oral route.
Group III rats were divided into two equal subgroups:
Group IIIa included six rats that were killed after 4 weeks.
Group IIIb included six rats that were killed after 12 weeks.
Group IV (rosuvastatin and coenzyme Q10-treated) comprised 12 rats. Each rat received rosuvastatin and coenzyme Q10 at the same previous doses and the same route of administration.
Group IV rats were divided into two equal subgroups:
Group IVa included six rats that were killed after 4 weeks.
Group IVb included six rats that were killed after 12 weeks.
At the end of each detected period, rats were killed by means of cervical dislocation and then skeletal muscle tissue samples were dissected. The samples were rapidly fixed in 3% glutaraldehyde for 3 h, and then processed for electron microscopic study. Other tissue samples were fixed in 10% formol saline for 5–7 days and washed in tap water. Thereafter, the samples were dehydrated in ascending grades of alcohol, cleared in xylene, and then impregnated in soft paraffin for 45 min, followed impregnation in hard paraffin for 45 min. Afterward, the samples were embedded in hard paraffin and oriented in blocks. Paraffin sections of 5–6 μm thickness were cut and stained with hematoxylin and eosin (H and E) and Mallory's trichrome stains for light microscopic studies.
On comparing average mitochondrial diameter in all studied groups, differences were regarded as highly significant (P< 0.01).
| Results|| |
Light microscopic results
Groups I and II (control groups)
Examination of H and E-stained sections of the gastrocnemius muscle of the control subgroups revealed normal structure of the skeletal muscle. It was formed of muscle fiber bundles separated by connective tissue (CT), perimysium [Table 1]. The muscle fibers were connected together by CT (endomysium). Some blood vessels were seen in the CT partitions of the muscle. In cross sections, skeletal muscle fibers appeared polygonal in shape [Figure 1]a. In longitudinal sections, the skeletal muscle fibers appeared long, parallel, cylindrical, and multinucleated with minimal variation in the fiber size. The sarcoplasm of the muscle fibers appeared eosinophilic and crossly striated. The nuclei were elongated and peripherally located under the sarcolemma [Figure 1]b.
|Table 1: Statistical analysis of the results according to average mitochondrial diameter in different study groups|
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|Figure 1: (a) A transverse section (group I) showing muscle fibers separated by endomysium (E). Bundles are separated by perimysium (P). Peripheral nuclei (arrows) (hematoxylin and eosin, ×400). (b) A longitudinal section (group II) showing parallel muscle fibers with clear transverse striations (S) and peripheral vesicular nuclei (arrows) (hematoxylin and eosin, ×1000). (c) A transverse section (group I) showing minimal collagen fibers between muscle fibers (arrows) (Measurement Ton (M.T.) ×400). (d) Electron microscope (group I) showing parallel myofibrils (mf) with light and dark bands. Sarcomeres are between two successive Z-lines (Z). The oval elongated nucleus (N) lies beneath the sarcolemma (sL) (microscopic magnification, ×4000).|
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In Mallory's trichrome-stained sections, a minimal amount of collagen fibers was observed between muscle fibers and around blood vessels [Figure 1]c.
Electron microscopic examination of the gastrocnemius muscle of control group rats showed normal ultrastructure appearance. The sarcoplasm appeared filled with myofibrils, which arranged parallel to the long axis of the myofiber. The myofibrils showed regular arrangement of alternating light (I) and dark bands (A). A pale narrow region, the H-band, was observed transecting the A band with a dark M-line within it. Z-line was seen bisecting the light band. Sarcomeres were detected between two successive Z-lines. Elongated nuclei were seen under the sarcolemma, with their heterochromatin distributed along the inner surface of the nuclear envelope and one or two nucleoli could be seen [Figure 1]d.
Group III [animals treated with a high therapeutic dose of rosuvastatin (0.5 mg/day)]
After 4 weeks of drug administration (subgroup IIIa), mild-to-moderate focal alterations were observed in sections of the gastrocnemius muscles of the rats used. Using H and E stain, longitudinal sections of muscle fibers showed splitting of the muscle fibers and loss of transverse striations, associated with mononuclear cellular infiltration and small pyknotic nuclei [Figure 2]a. Transverse sections of the muscle fibers showed variations in the size and shape of the fibers, with excess deposition of collagen fibers within the perimysium, associated with cellular infiltration. Blood vessels appeared dilated and congested [Figure 2]b.
|Figure 2: (a) A longitudinal section (subgroup IIIa) showing splitting and loss of striations (arrow), small pyknotic nuclei (arrow heads), infiltration (I), and hemorrhagic spots (H). Normal fibers (N) (hematoxylin and eosin, ×1000). (b) A transverse section (IIIa) of fibers with variable size and shape. Deposition of collagen within perimysium (P), infiltration (I), and blood vessel congestion (arrow) (hematoxylin and eosin, ×400). (c) A transverse section (IIIa) showing mild-to-moderate amount of collagen between muscle fibers (arrows) (M.T. ×400). (d) Electron microscope (IIIa) showing degeneration of myofibrils (mf), Mitochondria (m) of variable size and shape, and glycogen granules (arrows) (microscopic magnification, ×3000).|
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With Mallory's trichrome stain, transverse sections of the muscle showed mild-to-moderate amount of collagen fibers between muscle fibers and in the perimysium [Figure 2]c.
Electron microscopic examination of the gastrocnemius muscle of subgroup IIIa showed degeneration of some parts of myofibrils and accumulation of mitochondria of variable size and shape. Glycogen granules between the mitochondria were visible [Figure 2]d.
After 12 weeks of administration (subgroup IIIb), the changes included wider areas. Muscle fibers were more widely separated from each other, with loss of striations and complete degeneration of some parts. Mononuclear cellular infiltration was very heavy. Some muscle fibers were degenerated completely and showed vacuolation [Figure 3]a. Nuclei appeared internal and pyknotic associated with splitting and rounding of some fibers [Figure 3]b.
|Figure 3: (a) A longitudinal section (subgroup IIIb) showing clear vacuolation (V), infiltration (I), and areas of complete degeneration (arrows) (hematoxylin and eosin, ×400). (b) A transverse section (IIIb) showing mild variation in fiber size and shape with rounding of some fibers (arrow head), rounded internal nuclei (arrows), and m. fiber splitting (curved arrows) guided by internal nuclei (hematoxylin and eosin, ×400). (c) A transverse section (IIIb) showing extensive collagen in the endomysium (curved arrow) and perimysium (arrows) (M.T. ×400). (d) Electron microscope (IIIb) showing dilatation of sarcoplasmic reticulum cisternae (s) and partial loss of myofilaments (mf); two T-tubules per sarcomere (arrows) (microscopic magnification, ×5000).|
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Mallory's trichrome stain revealed a marked increase in collagen fibers between muscle fibers and bundles [Figure 3]c.
Electron microscopic examination of the gastrocnemius muscle of subgroup IIIb showed partial loss of myofibrils with disappearance of their Z-lines, and two T-tubules were seen per each sarcomere. There was dilatation of sarcoplasmic reticulum cisternae [Figure 3]d. Internal nucleus with irregular nuclear envelope and condensed heterochromatin was observed in some fibers. Fusion of the mitochondria to form giant vacuolated ones was very obvious. Diffuse glycogen granules were seen, especially in the subsarcolemmal space and in the intermyofibrillar spaces.
Group IV (animals treated with rosuvastatin and coenzyme Q10)
The histological picture of the gastrocnemius muscle of the animals treated with a high therapeutic dose of rosuvastatin (1.44 mg/day) and coenzyme Q10 at a dose of 3.6 mg/day for 4 weeks (subgroup IVa) was more or less similar to that of controls, except for minimal muscle fiber disintegration. Internal nuclei consisting a nuclear chain were noticed [Figure 4]a. Muscle fibers with peripheral condensed nuclei associated with blood vessel dilatation were detected [Figure 4]b. Deposition of collagen fibers was mild [Figure 4]c.
|Figure 4: (a) A longitudinal section (subgroup IVa) showing parallel m. fibers with clear striations (S) and internal nuclei forming a nuclear chain (arrow) (hematoxylin and eosin, ×1000). (b) A transverse section (IVa) showing m. fibers with distinct boundaries and peripheral condensed nuclei (arrows). Endomysium (E) showing blood vessel congestion (C) (hematoxylin and eosin, ×1000). (c) A transverse section (IVa) showing mild deposition of collagen fibers within the endomysium (arrows) (M.T. ×400). (d) Electron microscope (IVa) showing a small number of fused mitochondria (m) between myofibrils. Otherwise, the arrangement of myofibrils is similar to that of controls. Satellite cell (arrow) (microscopic magnification, ×3000).|
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Electron microscopic examination showed a small number of fused mitochondria between myofibrils [Figure 4]d. Otherwise, the myofibril arrangement was similar to that of controls.
After 12 weeks of drug administration (subgroup IVb), the H and E-stained sections showed mild focal histological changes. A transverse section of the muscle showed partial splitting and distortion of some muscle fibers [Figure 5]a. Areas of loss of transverse striations were observed in a longitudinal section associated with some hemorrhagic spots and mononuclear cellular infiltration [Figure 5]b. Mild-to-moderate deposition of collagen fibers was seen with Mallory's trichrome stain [Figure 5]c.
|Figure 5: (a) A transverse section (subgroup IVb) showing muscle fibers similar to that of controls, associated with partial distortion and splitting of some fibers (arrows). Notice perimysium (P) (hematoxylin and eosin, ×400). (b) A longitudinal section (IVb) showing splitting of muscle fibers with areas of loss of transverse striations (curved arrow), cellular infiltration (I), and some hemorrhagic spots (H) (hematoxylin and eosin, ×1000). (c) A transverse section (IVb) showing mild-to-moderate deposition of collagen within the perimysium (arrow) (M.T. ×400). (d) Electron microscopic (IVb) dilatation of sarcoplasmic reticulum cisternae (S), few mitochondria (m), and mild loss of myofibrils (mf) (microscopic magnification, ×4000).|
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Electron microscopic examination revealed apparent dilatation of some sarcoplasmic reticulum cisternae, few vacuolated mitochondria, and mild loss of myofibrils [Figure 5]d.
| Discussion|| |
Skeletal muscle consists of 40–50% of the body mass with more than 50% of overall metabolism taking place in them. Thus, optimal skeletal muscle function is extremely needed. The light microscopical structure of the skeletal muscle studied in the current work was similar to that described before.
Statin myopathy can present as a wide clinical spectrum ranging from mild myalgia to life-threatening rhabdomyolysis. Rhabdomyolysis is the rapid breakdown of skeletal muscle fibers due to muscle tissue injury. The most dangerous pathologic complication of rhabdomyolysis is acute renal failure. Different studies observed the occurrence of rhabdomyolysis during statin administration. Moreover, cerivastatin (Baycol) was withdrawn after numerous reports of rhabdomyolysis in 2001.
The present work was aimed to observe the potential myotoxicity of rosuvastatin using the light and transmission electron microscopes. Moreover, this study demonstrated the possible protective effect of coenzyme Q10 against rosuvastatin-induced muscle toxicity in animals. In this study, the gastrocnemius muscle was selected because most of its fibers are formed of type II white muscle fibers. Type II muscle fibers were reported by previous studies to be selectively vulnerable to statin-induced myotoxicity.
In the current study, different structural changes were detected in the gastrocnemius muscle using light microscope in group III rats receiving rosuvastatin. Sections of the gastrocnemius muscle obtained from rosuvastatin-treated rats revealed signs of muscle damage in both light and electron microscopy. At the light microscopic level, they showed muscular alterations in the form of variations in size, splitting, and degeneration of some muscle fibers, loss of cross striation, and mononuclear cellular infiltration in the affected fibers. Loss of cross striations has been considered as an indicator of myofilament damage. Mallory's trichrome stain was used and showed the presence of excess amounts of collagen around the affected fibers. At the electron microscopic level, the muscle sections showed myofibril loss, mitochondrial swelling and damage, and dilated sarcoplasmic reticulum cisterna. These findings at both levels were more pronounced in the group receiving rosuvastatin for 12 weeks. These histological changes were reported by the pathologists to be muscle myopathy and were similar to the findings of other researchers using a variety of statins.
The exact mechanism of how statins induce skeletal myotoxicity is not known. They prevent the conversion of HMG-CoA to mevalonic acid, which is an important step in cholesterol biosynthesis. Individual statins may have distinct effects on coenzyme Q10 synthesis (CoQ10, ubiquinone), which plays an important role in the production of muscle cell energy. It has been speculated that a reduction in ubiquinone in skeletal muscle may contribute to statin-induced muscle damage. Some studies have found that statins decrease plasma concentration and skeletal muscle of ubiquinone.
Atrogin-1, a muscle-specific ubiquitin protein ligase, may play an essential role in the toxicity of statins. Statins induce the expression of atrogin-1 with statin myopathy in humans and in several in-vitro models; in the models, myopathy might be prevented through the knockdown of atrogin-1. These and other proposed mechanisms need further experimental confirmation.
The apparent variation in fiber size detected in this work was previously recorded. It was explained as a result of atrophy and compensatory hypertrophy of some muscle fibers. They added that muscle atrophy might be brought about either by a reduction in protein synthesis or an enhancement of the normal rate of protein degradation or by both processes occurring simultaneously. Statin treatment inhibits the HMG-CoA reductase pathway, resulting in the impairment of protein synthesis with subsequent atrophy of muscle fibers.
In the present study, internal migration of subsarcolemmal nuclei and longitudinal splitting of muscle fibers were observed. It has been reported that muscle fiber splitting is an adaptive response, which occurs when the fiber reaches a critical size at which oxygen supply and metabolite exchange are no longer efficient. Moreover, it was suggested that nuclear migration plays an important role in the pathogenesis of muscle fiber splitting, and accordingly it can be concluded that such changes might occur in muscle fibers that have compensatory hypertrophy or undergone over work. Mononuclear cellular infiltration, which was observed in the present study in the CT of the muscle and in perivascular areas, could be related to the release of certain mediators during myocyte degeneration, which stimulate inflammatory reaction and attract inflammatory cells.
The progressive increase in the amount of collagen fibers was observed and was concomitant with the degree of muscle injury. It was stated that the increase in intrafasicular CT usually represents a response to myofiber loss, wherein fibroblasts replace the damaged area, with subsequent formation of collagen fibers.
The degenerative changes observed at both light and electron microscopy levels in this study were attributed to the cumulative effects on the sarcolemma of the muscle fibers leading to disturbance in the ion transporting system, thus initiating fiber degeneration. It was reported that statins inhibit HMG-CoA reductase, resulting in a low level of intracellular cholesterol, which is an important component of cell membranes, modulating their fluidity. Such changes could lead to alteration in the Na+/K+ pump function that predisposes to degeneration of the membranous organelles and irreversible damage to the cell.
It was reported that the inhibition of the HMG-CoA pathway deprives the cell from cholesterol and other important molecules such as coenzyme Q10, which is required in mitochondrial electron transport with subsequent mitochondrial dysfunction, impairment of energy production (ATP), cell physiology, and eventually cell degeneration. It was revealed that decreased chloride conductance and alterations in mitochondrial function induced by statins lead to an elevation in cytoplasmic Ca ++ concentration. Ca ++ overload leads to mitochondrial dysfunction and inhibition of mitochondrial respiration and uncouples oxidative phosphorylation, which lead to the failure of production of ATP and subsequently the failure of ion transport systems of the cellular membranes. Therefore, the myocyte injury and mitochondrial swelling observed in this study could be attributed to changed cell osmolarity.
It was also mentioned that morphological mitochondrial alterations are most frequently associated with defects of the respiratory chain. Subsarcolemmal accumulations and proliferation of mitochondria were explained as an attempt by the cell to compensate for the respiratory chain defect.
The previous results coincided with our observation and could explain the subsarcolemmal accumulation of mitochondria in this study. Moreover, the appearance of fused giant mitochondria in the present work could be attributed according to some researchers to the fact that cells are protected from mitochondrial dysfunction through complementation of DNA products in fused giant mitochondria and thus compensate for defects induced by various types of damage.
From the above discussion, it was obvious that various mechanisms were supposed to contribute to the pathogenesis of statin-induced muscle injuries. Inhibition of the HMG-CoA reductase pathway seemed to be one of them. This inhibition leads to deficiency in some compounds, especially coenzyme Q10, which is an important cofactor of the electron transport, as well as an essential antioxidant in mitochondria and lipid membranes. Its deficiency leads to mitochondrial dysfunction, impairment of energy production (ATP), derangement of cell physiology, and eventually cell degeneration.
The results obtained in the present research demonstrated that coadministration of rosuvastatin with coenzyme Q10 for group IV was effective in decreasing the severity of most of the histological alterations observed with rosuvastatin administration alone. These results coincided with previous studies, which reported that prophylaxis by the use of coenzyme Q10 decreased the frequency of musculoskeletal damage associated with lovastatin therapy and significantly decreased its severity and inhibited apoptosis, which could be induced by statins in cultured myoblasts. In addition, it was found that statin toxicity to lymphocytes in tissue culture of the human could be reversed through the addition of coenzyme Q10.
| Conclusion|| |
From the present study, it could be concluded that rosuvastatin drug caused damage of skeletal muscle in rats. This toxic effect of rosuvastatin could be attenuated when coenzyme Q10 is given concomitantly with it.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Steg G, Bhatt DL, Wilson PWF, D'Agostino Sr R, Ohman EM, Röther J, et al.
One-year cardiovascular event rates in outpatients with atherothrombosis. J Am Med assoc 2007; 297
Josan K, Majumdar SR, McAlister FA. The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. CMAJ 2008; 178
Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffmann C, et al.
Mevinolin: a highly potent competitive inhibitor of hydroxymethyl-co enzyme A reductase and a cholesterol lowering agent. Biochemistry 1980; 77
Abd El Salam EM, El Odemi M, Omar A, El-Serafy F, Abd El Hakim T, Samaka R, et al.
Effect of atorvastatin and erythropoietin on renal fibrosis induced by partial unilateral ureteral obstruction in rats. Menoufia Med J 2014; 27
Evans M, Rees A. Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same? Drug Saf 2002; 25
Takeda M, Noshiro R, Onozato ML, Tojo A, Hasannejab H, Huang X, et al.
Evidence for a role of human anion transporters in the muscular side effects of HMG-CoA reductase inhibitors. Eur J Pharmacol 2004; 483
White CM. A review of the pharmacologic and pharmacokinetic aspects of rosuvastatin. J Clin Pharmacol 2002; 42
McTaggart F, Buckett L, Davidson R, Holdgate G, McCormick A, Schneck D, et al.
Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001; 87
Siciliano G, Volpi L, Piazza S, Ricci G, Mancuso M, Murri L. Functional diagnostics in mitochondrial diseases. Biosci Rep 2007; 27
Shekelle P, Morton S, Hardy ML. Effect of supplemental antioxidants vitamin C, vitamin E and coenzymeQ10 for the prevention and treatment of cardiovascular disease. Evid Rep Technol Assess (Summ) 2003; 83
Mortensen SA, Leth A, Agner E, Rohde M. Dose related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med 1997; 18
C Chase. The Pink Sheet. FDC Rep 2004; 66:31.
Folkers K, Langsjoen P, Willis R, Richardson P, Xia LJ, Ye CQ, et al.
Lovastatin decreases coenzyme Q10 levels in humans. Proc Natl Acad Sci USA 1990; 87
Riechman SE, Lee CW, Chikani G, Chen VCW, Lee TV. Cholesterol and skeletal muscle health. World Rev Nutr Diet 2009; 100
Wooltorton E. Bayer pulls cerivastatin (Baycol) from market. CMAJ 2001; 165
Westwood FR, Bigley A, Randall K, Marsden AM, Scott RC. Statin-induced muscle necrosis in the rat: distribution, development and fibre selectivity. Toxicol Pathol 2005; 33
Akar H, Sarac A, Konuralp C, Yildiz L, Kolbakir F. Comparison of histopathologic effects of carnitine and ascorbic acid on reperfusion injury. Eur J Cardiothorac Surg 2001; 19
Cullen MJ, Johnson MA, Mastaglia FL. Pathological reactions of skeletal muscle. In: Mastaglia FL, Walton JN, editors. Skeletal muscle pathology
. Edinburgh, UK: Churchill Livingstone; 2001: 123–184.
Paiva H, Thelen KM, van Coster R. High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther 2005; 78
Hanai J, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J, et al.
The muscle-specific ubiquitin ligase atrogin-1/MAbx mediates statin-induced muscle toxicity. J Clin Invest 2007; 117
Owczarek J, Jasinska M, Orszulak Michalak D. Drug-induced myopathies: an overview of the possible mechanisms. Pharmacol Rep 2005; 57
Hassan NF, El- Bakry NA, Shalaby NM, Ghobara M, Bayomi N. Histological study of the effect of simvastatin on the skeletal muscle fibers in albino rat and the possible protective effect of coenzyme Q 10. Egypt J Histol 2009; 31
Lańcut M, Jedrych B, Lis-Sochocka M, Czerny K. Histological and ultrastructural changes in cross-striation muscle cells, under the influence of atorvastatin-HMG-CoA reductase inhibitor. Ann Univ Mariae Curie Sklodowska Med 2004; 59
Carvalho AA, Lima UW, Valiente RA. Statin and fibrate associated myopathy: study of eight patients. Arq Neuropsiquiatr 2004; 62
Sirvent P, Mercier J, Vassort G, Lacampagne A. Simvastatin triggers mitochondria-induced Ca 2+
signaling alteration in skeletal muscle. Biochem Biophys Res Commun 2005; 329
Nakahara K, Kuriyama M, Sonoda Y, Yoshidome H, Nakagawa H, Fujiyama J, et al.
Myopathy induced by HMG-CoA reductase inhibitors in rabbits: a pathological, electrophysiological and biochemical study. Toxicol Appl Pharmacol 1998; 152
Wakabayashi T. Megamitochondria formation: physiology and pathology. J Cell Mol Med 2002; 6
Palomaki A, Malminiemi K, Solakivi T, Malminiemi O. Ubiquinone supplementation during lovastatin treatment: effect on LDL oxidation ex vivo
. J Lipid Res 1998; 39
Kagan T, Davis C, Lin L, Zakeri Z. CoenzymeQ10 can in some circumstances block apoptosis and this effect is mediated through mitochondria. Ann N
Y Acad Sci 1999; 887
Pettit FH, Harper RF, Vilaythong J, Chu T, Shive W. Reversal of statin toxicity to human lymphocytes in tissue culture. Drug Metabol Drug Interact 2003; 19
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