doi: 10.1161/10.1161/01.ATV.0000194548.11901.a4
© 2005 American Heart Association, Inc.
Editorials |
Mechanisms of Statin-Induced Myopathy
A Role for the Ubiquitin–Proteasome Pathway?
From the Dyslipidemia and Atherosclerosis Research Unit (M.J.C., A.C.), National Institute for Health and Medical Research (INSERM); University Pierre et Marie Curie (M.J.C., A.C.); and Molecular Endocrinology Unit, Department of Medical Biochemistry, APHP (A.C.), Hopital de la Pitié, Paris, France.
Correspondence to M. John Chapman, PhD, DSc, Dyslipidemia and Atherosclerosis Research Unit, INSERM U.551, Hôpital de la Pitié, 83, Blvd de l’Hôpital, 75651 Paris Cedex 13, France. E-mail chapman{at}chups.jussieu.fr
The advent of the HMG-CoA reductase inhibitors, or statins, in the 1980’s as highly efficacious agents for the lowering of low-density lipoprotein-cholesterol (LDL-C) revolutionized treatment of hypercholesterolemia, a long established risk factor for premature coronary heart disease. Indeed, a recent prospective meta-analysis of data from more than 90 000 participants in 14 randomized clinical trials revealed that a statin-mediated reduction of 1 mmol/L (40 mg/dL) in LDL-C that is sustained for 5 years may produce a proportional reduction in major vascular events of some 23%.1 Greater reductions in LDL-C, which may be attained with intensive statin therapy as exemplified in the recent Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22), Treating to New Targets (TNT), and Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trials involving use of atorvastatin (80 mg/d), produce larger reductions in vascular disease risk.2–4 Importantly, risk reductions are proportional to the absolute reduction in LDL-C1, and moreover clinical benefit may be apparent with intensive statin treatment as early as 30 days after initiation in acute coronary syndrome patients, with significant decrement in cardiovascular morbi-mortality.5
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Statins not only exhibit a remarkably high benefit to risk ratio, but are equally characterized by a safety profile with excellent tolerance.6,7 Nonetheless, statins may exert toxic effects on skeletal muscle which are generally referred to as myopathy, and whose overall incidence is typically <0.1% of patients receiving statin monotherapy.6 Although myopathy can refer to any muscular disease, the recent clinical advisory on the use and safety of statins differentiated myalgia as muscle ache or weakness in the absence of elevation in creatine kinase (CK), and myositis as adverse muscular symptoms associated with increased CK levels.7 Rhabdomyolysis is a severe form of myositis involving myoglobulinuria, which can engender acute renal failure. Although rhabdomyolysis associated with statin treatment is very rare (less than one fatal case per 5 million patients), nevertheless muscular pain and weakness are more frequent and may affect 7% of patients on statin monotherapy, with myalgia contributing up to 25% of all adverse events associated with statin use.8 The effects of these subclinical muscular side effects should not be underestimated, however, as they reduce patient compliance with possible discontinuation of therapy, limit physical activity, reduce the quality of life, and most importantly, may ultimately deprive the dyslipidemic patient at high CV risk of the clinical benefit of statin treatment. Such muscular symptoms become especially pertinent in the context of recent clinical trials which have validated optimized reduction of CV morbi-mortality using high-dose statin therapy, and particularly as increase in statin dosage is closely associated with increased risk of muscular side effects.6,8 Despite the widespread use of statin therapy worldwide, the mechanism(s) underlying statin-induced myopathy remain controversial and poorly understood.9 It is in this scenario that Urso and colleagues in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, by focusing on the capacity of statins to modify muscular response to exercise stress and by applying state-of-the-art microarray technology to muscle biopsy tissue from healthy volunteers, provide us with the novel concept that enhanced protein degradation via the ubiquitin proteasome pathway may represent a key mechanism underlying statin myalgia.10
The experimental protocol merits special consideration. Gene profiles in skeletal muscle (vastus lateralis) of young normolipidemic male volunteers (n=8) randomized to either placebo or high-dose atorvastatin (80 mg/d) treatment for 4 weeks were compared on a microarray representing 14 500 well-characterized genes. A program of eccentric leg exercise was superimposed on this protocol at baseline and after treatment or placebo; bilateral muscle biopsies were obtained 8 hours after exercise at baseline and after 4 weeks, one leg having been exercised, the other unexercised leg acting as control. In this way, a total of 4 biopsies were obtained for each subject, with both unexercised and exercised biopsies at baseline and after treatment or placebo; each patient acted as his own control, thus limiting interindividual variability. All subjects were free of muscular symptoms and exhibited normal CK levels throughout the protocol.
On the specific basis of comparison of gene profiles in nonexercised legs at baseline and 4 weeks, expression of only 2 genes was significantly changed, thus lending support to the authors’ hypothesis that low physiological variability in gene expression occurred with time and between legs. When comparing exercised to nonexercised legs, numerous genes (80) were expressed differentially between legs and were primarily involved in cell cycling and growth, signal transduction, transcription, and protein metabolism. Statin treatment without exercise was associated with only 5 differentially-expressed genes of which 2 were calmodulin and a tumor suppressor protein with ubiquitin conjugating enzyme activity; by contrast, eccentric muscle-damaging exercise plus statin increased this expression profile by 11-fold. When grouped into functional categories, the most marked effects of statin on gene expression were seen on transcription and protein degradation via the ubiquitin proteasome (UP) pathway (increments of 14% to 23% and of 8% to 18%, respectively). The expression patterns of 4 genes in this latter pathway (FBX32, FBX03, RNF128, and UBE2M) were then explored by QRT-PCR assay of tissue mRNA levels, with confirmation of the upregulation of FBX03 (E3 ligase), RNF128, and UBE2ML (E2 conjugating enzyme). Significantly, increases in mRNAs for components of the UP pathway in human skeletal muscle after eccentric exercise in the absence of statin treatment were reported earlier.11,12 How then does statin treatment impact on alterations in protein turnover in skeletal muscle stimulated by eccentric exercise with myofibrillar damage ?
In mammalian cells, the ubiquitin-proteasome–dependent proteolytic pathway catalyzes the selective breakdown of abnormal and short-lived proteins (eg, oncoproteins, tumor suppressors, transcriptional factors, cell-cycle regulators).13 In skeletal muscle, this pathway is also responsible for the breakdown of long-lived myofibrillar proteins, including actin and myosin.14 There are 2 major steps in this pathway. First, substrates are polyubiquitinated in a process that is tightly controlled by ubiquination enzymes.13 Polyubiquitination requires the sequential involvement of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and finally ubiquitin-protein ligase (E3) that recognize substrates of the ubiquitin system and conjugates ubiquitin to them. These ubiquitin ligases form an exceptionally large protein family, with >500 distinct E3 ligases in mammalian species. In a second step, polyubiquitinated substrates are selectively recognized and degraded by the 26S proteasome.14
By virtue of the regulation of levels of intracellular proteins, ubiquitin-dependent proteolysis (degradation) mediates a great variety of cellular and metacellular (organismal) functions, including cell growth, division, differentiation, signal transduction, stress response, programmed cell death, embryogenesis, immunity, and activities of the nervous system. Indeed, it is now clear that protein degradation rivals, and frequently surpasses, classical regulation of protein mass by transcription and translation in significance.14
In contrast to the UP pathway, upregulation of genes of protein catabolism, which typically target complex muscle structures, enhance cleavage of large structural proteins whose degradation may be completed by the UP system. To account for changes in protein degradative machinery potentiated by muscle stress superimposed on a background of statin treatment, the authors propose the hypothesis that insertion of a statin into the myocyte cell membrane may induce a degree of instability when subjected to eccentric exercise stress, triggering activation of intracellular proteolytic cascades.15 Such a hypothesis is consistent with the observed elevation in a series of genes implicated in protein catabolism, in addition to those of the UP system. To what degree such cell membrane instability may be related (1) to statin lipophilicity index, (2) to statin dose, (3) to statin plasma half-life and pharmacokinetic characteristics, and (4) to cumulative exposure of muscle tissue to individual statins and their metabolites, remains indeterminate.
In addition to alterations in expression profiles of genes implicated in protein turnover, marked reductions in apoptotic (4-fold) and in inflammatory gene expression with increase in transcriptional genes were equally induced by statin treatment on a background of muscle damage. These findings raise the possibility that statin plus exercise attenuates programmed muscle cell death versus exercise alone, thereby potentiating processes of cellular repair, while concomitantly suppressing genes of the inflammatory response, a potentially synergic protective effect.
The elegant studies of Urso et al10 do not allow evaluation of the possibility that mechanisms in addition to the UP pathway may contribute to the effects of statins on skeletal muscle metabolism. Indeed, the small number of subjects and high stringency applied to changes in gene expression may have underpowered the potential to detect modulation of key biological pathways. Such is the case for genes encoding mitochondrial proteins, as 4 genes were downregulated in the range of 1.1- to 1.4-fold, failing the stringency criterion for 1.5-fold change with P<0.005. Equally, minor effects of statin plus exercise were observed for genes of cholesterol metabolism (eg, 1.25-fold downregulation of the LDL receptor gene). These findings are not inconsistent with data in the literature on the effect of high-dose statin therapy on cholesterol and ubiquinone metabolism in human skeletal muscle and on mitochondrial function. Thus the data of Paiva et al16 indicate that statins alter skeletal muscle sterol metabolism detected as a marked decrease (up to 66%) in lathosterol:cholesterol ratio, a marker of cholesterologenesis, but also occasionally detected as reduced muscle ubiquinone levels. Moreover, lipid droplet accumulation in muscle biopsies of patients with muscular symptoms is indicative of increase in both sterol and lipid content on statin treatment.17 Furthermore, interpretation of mitochondrial function assays suggests that a decrease in mitochondrial number or volume, or both, occurs, which of itself may explain statin-induced myalgia without CK elevation16; such pathology may precede more severe muscular symptomatology.
While highlighting the modulation of genes of the UP pathway as key targets of exercise stress and muscular damage associated with statin treatment, the studies of Urso et al10 serve to emphasize yet again our partial comprehension of the mechanisms underlying the potential myotoxicity of statins, particularly at high dose18,19 (Figure). Indeed, given that ubiquitin ligases such as FBX03 show high substrate specificity for concerted protein degradation by the UP pathway, it is of special interest to determine its protein target(s); in this way, the interactive interface between exercise-induced muscle damage and statin treatment may be identified.
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Finally, it should be emphasized that new research initiatives are urgently required in this important therapeutic area; such efforts should be focused on the impact of statins on mitochondrial function and biogenesis, on membrane stability, on lipid and sterol metabolism, on protein turnover, on cell turnover, and on signaling cascades in muscle tissue.
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Acknowledgments |
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We are indebted to Mme Françoise Berneau for preparation of the manuscript and figure.
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Related Article:
- Changes in Ubiquitin Proteasome Pathway Gene Expression in Skeletal Muscle With Exercise and Statins
- Maria L. Urso, Priscilla M. Clarkson, Dustin Hittel, Eric P. Hoffman, and Paul D. Thompson
Arterioscler. Thromb. Vasc. Biol. 2005 25: 2560-2566.[Abstract] [Full Text] [PDF]
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