Editorial
Mechanisms of Statin-Induced Myopathy
A Role for the Ubiquitin–Proteasome Pathway?
M. John Chapman, Alain Carrie
T
he 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 (RE-
VERSAL) trials involving use of atorvastatin (80 mg/d),
produce larger reductions in vascular disease risk.2– 4 Impor-
tantly, risk reductions are proportional to the absolute reduc-
tion 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
See page 2560
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 Rhabdomy-
olysis is a severe form of myositis involving myoglobulin-
uria, which can engender acute renal failure. Although
rhabdomyolysis associated with statin treatment is very rare
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 Endo-
crinology 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@chups.jussieu.fr
(Arterioscler Thromb Vasc Biol. 2005;25:2441-2444.)
© 2005 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
DOI: 10.1161/10.1161/01.ATV.0000194548.11901.a4
2441 at Harvard University on June 25, 2015
Downloaded from http://atvb.ahajournals.org/
(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 con-
text of recent clinical trials which have validated optimized
reduction of CV morbi-mortality using high-dose statin ther-
apy, 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, Throm-
bosis, 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 mecha-
nism 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 trans-
2442 Arterioscler Thromb Vasc Biol. December 2005

Responses of skeletal muscle to statin monotherapy. Statins exert effects on skeletal muscle gene expression in both resting and exer-
cise stress conditions. Under these conditions, activation of the expression of component genes of the UP pathway of protein degrada-
tion occurs. When muscle-damaging eccentric exercise is superimposed on statin treatment, such activation targets both ubiquitin-
conjugating enzymes (E2) and ubiquitin ligases (E3), and notably the FBX03 gene. Upregulation of the expression of genes of the UP
pathway associated with myofibrillar damage favors enhanced degradation of muscle proteins with increased protein turnover. The
impact of statins on skeletal myocytes may occur via insertion of the statin molecule into the cell membrane, which in turn may potenti-
ate membrane instability under exercise stress. Exposure of skeletal muscle to statins and their metabolites equally involves effects on
muscle metabolism independently of exercise. Such effects may arise not only from statin-membrane interactions, but also from inhibi-
tion of cholesterol synthesis, with decreased concentrations of intermediates such as ubiquinone/ubiquinol. In addition, intracellular
lipid and sterol accumulation in muscle tissue are well documented. Finally, reduction in mitochondrial number or volume, or both, in
myocytes is established, thereby constituting a direct link to muscle weakness in the absence of CK elevation. In this way, myopathy
may be potentiated.

duction, transcription, and protein metabolism. Statin treat-
ment 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 pro-
teasome (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
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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 Polyubiquitina-
tion requires the sequential involvement of ubiquitin-
activating enzyme (E1), ubiquitin-conjugating enzyme (E2),
and finally ubiquitin-protein ligase (E3) that recognize sub-
strates 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
 Chapman and Carrie
By virtue of the regulation of levels of intracellular
proteins, ubiquitin-dependent proteolysis (degradation) medi-
ates 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 sys-
tem. 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 poten-
tiated 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 proteo-
lytic 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 apoptot-
ic (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 pro-
grammed 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 recep-
tor gene). These findings are not inconsistent with data in the
literature on the effect of high-dose statin therapy on choles-
terol 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:cho-
lesterol 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
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Mechanisms of Statin-Induced Myopathy 2443
both sterol and lipid content on statin treatment.17 Further-
more, interpretation of mitochondrial function assays sug-
gests 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.
Finally, it should be emphasized that new research initia-
tives 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 stabil-
ity, on lipid and sterol metabolism, on protein turnover, on
cell turnover, and on signaling cascades in muscle tissue.
Acknowledgments
We are indebted to Mme Françoise Berneau for preparation of the
manuscript and figure.
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Mechanisms of Statin-Induced Myopathy: A Role for the Ubiquitin−Proteasome Pathway?
M. John Chapman and Alain Carrie

Arterioscler Thromb Vasc Biol. 2005;25:2441-2444

doi: 10.1161/10.1161/01.ATV.0000194548.11901.a4
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