0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Muscle Coenzyme Q10 Level in Statin-Related Myopathy FREE

Costanza Lamperti, MD; Ali B. Naini, PhD; Valeria Lucchini, MD; Alessandro Prelle, MD; Nereo Bresolin, MD; Maurizio Moggio, MD; Monica Sciacco, MD; Petra Kaufmann, MD; Salvatore DiMauro, MD
[+] Author Affiliations

Author Affiliations: Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Unita’ Operativa, Neurologia, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore Policlinico, University of Milan, Milan, Italy (Drs Lamperti, Lucchini, Prelle, Bresolin, Moggio, and Sciacco); and Department of Neurology, Columbia University Medical Center, New York, NY (Drs Naini, Kaufmann, and DiMauro).


Arch Neurol. 2005;62(11):1709-1712. doi:10.1001/archneur.62.11.1709.
Text Size: A A A
Published online

Background  Statin drugs (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce the level of cholesterol by inhibiting the synthesis of mevalonate, an intermediary in the cholesterol biosynthetic pathway. Use of statin drugs has been associated with a variety of skeletal muscle–related complaints. Coenzyme Q10 (CoQ10), a component of the mitochondrial respiratory chain, is also synthesized from mevalonate, and decreased muscle CoQ10 concentration may have a role in the pathogenesis of statin drug–related myopathy.

Objectives  To measure the CoQ10 concentration and respiratory chain enzyme activities in muscle biopsy specimens from 18 patients with statin drug–related myopathy and to look for evidence of apoptosis using the TUNEL (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling) assay.

Design  An open-labeled study of CoQ10 concentration in muscle from patients with increased serum creatine kinase concentrations while receiving standard statin drug therapy.

Setting  Neuromuscular centers at 2 academic tertiary care hospitals.

Results  Muscle structure was essentially normal in 14 patients and showed evidence of mitochondrial dysfunction and nonspecific myopathic changes in 2 patients each. Muscle CoQ10 concentration was not statistically different between patients and control subjects, but it was more than 2 SDs below the normal mean in 3 patients and more than 1 SD below normal in 7 patients. There was no TUNEL positivity in any patients.

Conclusion  These data suggest that statin drug–related myopathy is associated with a mild decrease in muscle CoQ10 concentration, which does not cause histochemical or biochemical evidence of mitochondrial myopathy or morphologic evidence of apoptosis in most patients.

Figures in this Article

Statin drugs (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are widely prescribed drugs that reduce blood cholesterol levels by inhibiting the synthesis of mevalonate, a critical intermediary in the cholesterol pathway. Statin drug therapy has been associated with a variety of muscle complaints, ranging from myalgia and cramps to exercise intolerance, weakness, and, occasionally, acute muscle breakdown with myoglobinuria.1,2 Serum creatine kinase (CK) levels are elevated in all of these conditions.2 It is curious that muscle symptoms and high serum CK levels often persist even after statin drug withdrawal.2

Coenzyme Q10(CoQ10), a lipophilic component of the electron transport chain, transfers electrons from complexes I and II to complex III, and it also is an antioxidant and a membrane stabilizer. While it was clearly shown that atorvastatin decreases the concentration of blood CoQ10 in patients with hyperchlolesterolemia,3 a similar effect of statin drugs on muscle CoQ10 has not been documented. In addition, studies in rat and in human muscle cultures suggested that statin drugs induce apoptosis but not CoQ10 deficiency.4 To investigate a possible correlation between statin drug–related myopathy and CoQ10 deficiency, we studied muscle biopsy specimens from 18 patients with statin drug–related muscle symptoms or high serum CK levels. We correlated muscle structure with CoQ10 concentration, respiratory chain complex III activity, and evidence of apoptosis, using the TUNEL (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling) assay and immunohistochemistry with antibodies against caspase-3, Bax, and Bcl-2).

PATIENTS

We examined 18 patients with hypercholesterolemia (8 men, 10 women), aged 31 to 76 years, who were receiving statin drugs. Eight of 18 patients had both weakness and myalgia, 4 patients had only weakness, 3 patients had only myalgia, and 5 patients reported cramps (Table 1). The weakness was proximal more than distal, not severe (Medical Research Council scales 4+ [mild] to 5− [very mild]). Two patients (patients 1 and 4 [Table 1]) had symptoms and underwent muscle biopsy because of persistently high serum CK values. Serum CK levels ranged between 200 and 1500 U/L (normal, <195 U/L), but 1 patient (patient 10) had values as high as 18 000 IU.

Table Graphic Jump LocationTable 1. Clinical Data in 18 Patients With Statin Drug–Related Myopathy

Six patients were receiving simvastatin; 5, cerivastatin; 3, atorvastatin; and 1, rosuvastatin, at dosages of 5 mg/d (1 patient), 10 mg/d (9 patients), or 20 mg/d (5 patients). Neither type of statin drug nor dosage was known in 3 patients. Electromyography was performed in 15 patients and demonstrated myopathic changes in 6 patients, neuropathic changes in 3 patients, and normal findings in 6 patients (Table 1).

MORPHOLOGY AND BIOCHEMISTRY

Muscle histochemistry and measurements of respiratory chain enzymes in muscle extracts were performed using described techniques.5,6 Immunohistochemical reactions for both proapoptotic (TUNEL, Bax, and caspase-3) and antiapoptotic (Bcl-2) markers were carried out in serial cryostat cross sections.7 The TUNEL assay was performed according to the manufacturer's instructions (In Situ Cell Death Detection Kit; Roche Applied Science, Mannheim, Germany). As for the proapoptotic and antiapoptotic markers (Santa Cruz Biotechnology, Santa Cruz, Calif), anti-Bax was a rabbit polyclonal antibody raised against the amino terminus of human Bax, anti–caspase-3 was a goat polyclonal antibody raised against the amino terminus of the human caspase-3 p11 subunit, and anti–Bcl-2 was a mouse monoclonal antibody obtained by fusing myeloma cells with spleen cells from an immunized mouse. As secondary antibody, we used antimouse IgG. The reactions were developed with 3,3′-diaminobenzidine using the avidin-biotin complex–immunoperoxidase vector amplified system (Vectastain Elite ABC Kit; Vector Laboratories, Burlingame, Calif), as previously described.7

Coenzyme Q10 was extracted from muscle (50 μL of muscle homogenate and 950 μL of ice-cold 1-propanol) by vortex mixing in a microcentrifuge tube for 2 minutes; after centrifugation at 14 000 rpm for 10 minutes at 4°C, 30 μL of clear supernatant was injected directly into the high-performance liquid chromatographic system. High-performance liquid chromatographic analyses were performed using a reverse-phase isocratic system, as previously described.8

Muscle structure was normal or showed mild myopathic changes in 14 patients. In 2 patients (patients 7 and 8 [Table 2]), there were a few necrotic and vacuolated fibers. Only 2 patients demonstrated some evidence of mitochondrial dysfunction: 5 cytochrome c oxidase–negative ragged red fibers were seen in the biopsy specimen from 61-year-old patient 10, and 2 cytochrome c oxidase–negative fibers were seen in the biopsy specimen from 63-year-old patient 11 (Table 2).

The levels of muscle CoQ10 in our patients as a group were not significantly different from those in control subjects (median values, 29.5 μg/g in patients vs 32.0 in 118 controls; P>.05, Mann-Whitney rank sum test). However, muscle CoQ10 concentration was below 2 SDs of the normal mean in 3 patients and below 1 SD in 7 patients (10 [56%] of 18 patients). In the remaining 8 patients the concentration of muscle CoQ10 was normal (±1 SD of the mean) in 4 patients and increased (>2 SDs) in 4 patients (Figure). There was no clear correlation between muscle structure and CoQ10 concentration, but the 2 patients (patients 10 and 11) with a few ragged red fibers or cytochrome c oxidase–negative fibers had CoQ10 levels at or below 1 SD of the mean. One of the 2 (patient 10) also had the highest serum CK levels. Complex III activity was normal in all patients.

Place holder to copy figure label and caption
Figure.

Scattergram of muscle coenzyme Q10 concentrations in 18 patients with statin drug–related myopathy and 118 control subjects. Horizontal bars represent the median for each group.

Graphic Jump Location

The TUNEL assay and immunohistochemical studies with antibodies against Bax, Bcl−2, and caspase−3 were performed in the 11 patients from whom enough tissue was available; all of these tests yielded negative results in all 11 patients.

In developed countries, statin drugs are among the most frequently administered drugs used to lower the blood cholesterol level and prevent cardiovascular disease and stroke. Usually they are well tolerated and safe, but in fewer than 1% of patients they cause muscle problems, usually exercise-related myalgia and cramps, less commonly fixed weakness, and occasionally acute muscle breakdown (rhabdomyolysis) and myoglobinuria.2 The incidence of myopathy seems to be similar for different statin drugs.

The pathogenesis of statin drug–related myopathy is unknown.9,10 An attractive hypothesis is that muscle symptoms may be due to a partial defect of CoQ10, because CoQ10 and cholesterol share a common biosynthetic pathway that is inhibited by statin drugs. This concept is supported by findings in blood samples from patients with hypercholesterolemia, in whom CoQ10 concentration decreased to 50% of baseline values after 30 days of treatment with atorvastatin,3 although the dosage of statin (80 mg/d) was considerably higher than in our patients (5−20 mg/d). Indirect support for this hypothesis comes from knowledge that severe, and presumably primary, muscle CoQ10 deficiency causes mitochondrial myopathic changes with exercise intolerance and recurrent myoglobinuria.1115 Less severe muscle CoQ10 deficiency is associated with a syndrome dominated by cerebellar ataxia but often accompanied by muscle weakness.1618 In patients with ataxic CoQ10 deficiency muscle biopsy tissue is usually normal or nonspecifically myopathic and the activity of complex III of the respiratory chain is inconsistently decreased.

To shed some light on the role of CoQ10 in the pathogenesis of statin drug–related myopathy we studied the muscle biopsy specimens from 18 patients given standard doses of statin drugs to treat hypercholesterolemia with reports of muscle pain, cramps, and weakness (16 patients) or with increased levels of serum CK in the absence of symptoms (2 patients). We found decreased muscle CoQ10 concentration in 10 patients (56%), but the decrease was slight (<1 SD of the normal mean) in 7 patients (70%) and severe (<2 SDs) in only 3 patients (30%). None of the 3 patients (patients 3, 16, and 17) with the lowest CoQ10 concentrations had abnormal muscle structure or biochemical changes. Conversely, the 2 patients (patients 10 and 11) with some morphologic evidence of mitochondrial dysfunction had only modest decreases in muscle CoQ10concentrations. In addition, both patients were older than 60 years, which raises the possibility that the few ragged red fibers and cytochrome c oxidase–negative fibers in their biopsy specimens may have been related to aging rather than to CoQ10 deficiency. The increased muscle concentrations of CoQ10 in 4 patients (patients 6, 7, 8, and 14) are difficult to explain, unless these patients were taking vitamin supplements containing CoQ10, a possibility we could not exclude with certainty.

Because the muscle biopsy specimens from 2 young brothers with myopathic CoQ10 deficiency showed florid apoptosis,13 and studies in rat and in human muscle cultures exposed to statin drugs had also shown activation of apoptotic pathways (without CoQ10 deficiency),4 we looked for evidence of apoptosis in our patients, but found none.

In summary, our data suggest that statin drugs may decrease the concentration of CoQ10 in muscle to a modest extent in some patients. Although these data do not support a pathogenic role of CoQ10 deficiency in statin drug–related myopathy, it may be prudent to advocate that patients with statin drug–related myopathy be given oral CoQ10 supplementation.

Correspondence: Salvatore DiMauro, MD, 4−420 College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032 (sd12@columbia.edu).

Accepted for Publication: June 23, 2005.

Author Contributions:Study concept and design: Prelle, Bresolin, Moggio, Kaufmann, and DiMauro. Acquisition of data: Lamperti, Naini, and Lucchini. Analysis and interpretation of data:Lamperti, Naini, Sciacco, Kaufmann, and DiMauro. Drafting of the manuscript: Lamperti and Naini. Critical revision of the manuscript for important intellectual content: Lucchini, Prelle, Moggio, and Sciacco. Statistical analysis: Lamperti, Naini, and Kaufmann. Obtained funding: Lamperti and DiMauro. Administrative, technical, and material support: Lucchini and DiMauro. Study supervision: Prelle, Bresolin, and Moggio.

Funding/Support: This study was supported by Association Amici del Centro Dino Ferrari, University of Milan, Milan, Italy; the Telethon Project QLTR−2001−02769; grants NS11766 and HD32062 from the National Institutes of Health, Bethesda, Md; a grant from the Muscular Dystrophy Association, Tucson, Ariz; and the Marriott Mitochondrial Disorder Clinical Research Fund (MMDCRF), Chevy Chase, Md.

Acknowledgment: The “Criobanca Automatizzata di Materiale Biologico” is gratefully acknowledged for providing frozen muscle biopsy specimens.

Hodel  C Myopathy and rhabdomyolysis with lipid−lowering drugs. Toxicol Lett 2002;128159- 168
PubMed Link to Article
Thompson  PDClarkson  PKaras  RH Statin−associated myopathy. JAMA 2003;2891681- 1690
PubMed Link to Article
Rundek  TNaini  ASacco  RCoates  KDiMauro  S Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol 2004;61889- 892
PubMed Link to Article
Johnson  TEZhang  XBleicher  KB  et al.  Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone. Toxicol Appl Pharmacol 2004;200237- 250
PubMed Link to Article
Sciacco  MPrelle  AComi  GP  et al.  Retrospective study of a large population of patients affected with mitochondrial disorders: clinical, morphological and molecular genetic evaluation. J Neurol 2001;248778- 788
PubMed Link to Article
DiMauro  SServidei  SZeviani  M  et al.  Cytochrome c oxidase deficiency in Leigh syndrome. Ann Neurol 1987;22498- 506
PubMed Link to Article
Fagiolari  GSciacco  MChiveri  L  et al.  Lack of apoptosis in patients with progressive external ophthalmoplegia and mutated adenine nucleotide translocator−1 gene. Muscle Nerve 2002;26265- 269
PubMed Link to Article
Naini  AJackson−Lewis  VHirano  MDiMauro  S Primary coenzyme Q10 deficiency and the brain. Biofactors 2003;18145- 152
PubMed Link to Article
Owczarek  JJasinska  MOrszulak−Michalak  D Drug−induced myopathies: an overview of the possible mechanisms. Pharmacol Rep 2005;5723- 34
PubMed
Baker  SK Molecular clues into the pathogenesis of statin−mediated muscle toxicity. Muscle Nerve 2005;31572- 580
PubMed Link to Article
Ogasahara  SEngel  AGFrens  DMack  D Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A 1989;862379- 2382
PubMed Link to Article
Sobreira  CHirano  MShanske  S  et al.  Mitochondrial encephalomyopathy with coenzyme Q10 deficiency. Neurology 1997;481238- 1243
PubMed Link to Article
Di Giovanni  SMirabella  MSpinazzola  A  et al.  Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurology 2001;57515- 518
PubMed Link to Article
Aure  KBenoist  JFOgier de Baulny  HRomero  NBRigal  OLombes  A Progression despite replacement of a myopathic form of coenzyme Q10 defect. Neurology 2004;63727- 729
PubMed Link to Article
Lalani  SVladutiu  GDPlunkett  KLotze  TEAdesina  AMScaglia  F Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency. Arch Neurol 2005;62317- 320
PubMed Link to Article
Musumeci  ONaini  ASlonim  AE  et al.  Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology 2001;56849- 855
PubMed Link to Article
Lamperti  CNaini  AHirano  M  et al.  Cerebellar ataxia and coenzyme Q10 deficiency. Neurology 2003;601206- 1208
PubMed Link to Article
Gironi  MLamperti  CNemni  R  et al.  Late−onset cerebellar ataxia with hypogonadism and muscle coenzyme Q10 deficiency. Neurology 2004;62818- 820
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Scattergram of muscle coenzyme Q10 concentrations in 18 patients with statin drug–related myopathy and 118 control subjects. Horizontal bars represent the median for each group.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Clinical Data in 18 Patients With Statin Drug–Related Myopathy

References

Hodel  C Myopathy and rhabdomyolysis with lipid−lowering drugs. Toxicol Lett 2002;128159- 168
PubMed Link to Article
Thompson  PDClarkson  PKaras  RH Statin−associated myopathy. JAMA 2003;2891681- 1690
PubMed Link to Article
Rundek  TNaini  ASacco  RCoates  KDiMauro  S Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol 2004;61889- 892
PubMed Link to Article
Johnson  TEZhang  XBleicher  KB  et al.  Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone. Toxicol Appl Pharmacol 2004;200237- 250
PubMed Link to Article
Sciacco  MPrelle  AComi  GP  et al.  Retrospective study of a large population of patients affected with mitochondrial disorders: clinical, morphological and molecular genetic evaluation. J Neurol 2001;248778- 788
PubMed Link to Article
DiMauro  SServidei  SZeviani  M  et al.  Cytochrome c oxidase deficiency in Leigh syndrome. Ann Neurol 1987;22498- 506
PubMed Link to Article
Fagiolari  GSciacco  MChiveri  L  et al.  Lack of apoptosis in patients with progressive external ophthalmoplegia and mutated adenine nucleotide translocator−1 gene. Muscle Nerve 2002;26265- 269
PubMed Link to Article
Naini  AJackson−Lewis  VHirano  MDiMauro  S Primary coenzyme Q10 deficiency and the brain. Biofactors 2003;18145- 152
PubMed Link to Article
Owczarek  JJasinska  MOrszulak−Michalak  D Drug−induced myopathies: an overview of the possible mechanisms. Pharmacol Rep 2005;5723- 34
PubMed
Baker  SK Molecular clues into the pathogenesis of statin−mediated muscle toxicity. Muscle Nerve 2005;31572- 580
PubMed Link to Article
Ogasahara  SEngel  AGFrens  DMack  D Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A 1989;862379- 2382
PubMed Link to Article
Sobreira  CHirano  MShanske  S  et al.  Mitochondrial encephalomyopathy with coenzyme Q10 deficiency. Neurology 1997;481238- 1243
PubMed Link to Article
Di Giovanni  SMirabella  MSpinazzola  A  et al.  Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurology 2001;57515- 518
PubMed Link to Article
Aure  KBenoist  JFOgier de Baulny  HRomero  NBRigal  OLombes  A Progression despite replacement of a myopathic form of coenzyme Q10 defect. Neurology 2004;63727- 729
PubMed Link to Article
Lalani  SVladutiu  GDPlunkett  KLotze  TEAdesina  AMScaglia  F Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency. Arch Neurol 2005;62317- 320
PubMed Link to Article
Musumeci  ONaini  ASlonim  AE  et al.  Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology 2001;56849- 855
PubMed Link to Article
Lamperti  CNaini  AHirano  M  et al.  Cerebellar ataxia and coenzyme Q10 deficiency. Neurology 2003;601206- 1208
PubMed Link to Article
Gironi  MLamperti  CNemni  R  et al.  Late−onset cerebellar ataxia with hypogonadism and muscle coenzyme Q10 deficiency. Neurology 2004;62818- 820
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 70

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Statins, coenzyme Q10 and diabetes type 2. Bratisl Lek Listy 2014;115(2):112.
A current approach to statin intolerance. Clin Pharmacol Ther 2014;96(1):74-80.
JAMAevidence.com

Users' Guides to the Medical Literature
Clinical Scenario

Users' Guides to the Medical Literature
Statin Dosing and LDL Levels