Introduction
Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase,
have revolutionized the management of cardiovascular disease. Statins decrease
cardiovascular disease morbidity and mortality by about 25%. The number of individuals
using statins will continue to rise due to the rising incidence of cardiovascular disease and
due to the ongoing research efforts into investigational uses of statins. Thus, millions of
patients worldwide now receive statins for hypercholesterolemia, with more than 13 million
patients in the United States alone [1].
However, 0.5% – 15% of statin recipients developed adverse effects on skeletal muscles,
ranging from slight myalgia to severe rhabdomyolysis [2], including the reports on reduction
of muscle contractility in humans [3] and rats [4]. Yet, no specific definition of statin
myopathy exists. The American College of Cardiology (ACC), American Heart Association
(AHA), National Heart, Lung and Blood Institute (NHLBI), U.S. Food and Drug
Administration (FDA), and National Lipid Association (NLA) have each proposed
definitions for statin-associated muscle effects, which do not give specific differentiation
between statin related myopathy i.e myopathy, myalgia, myositis (Table- 1).
Many studies have been shown that the rate of myopathy for patients on statins is somewhat
higher and different from that of age and gender matched non-statin cardiac patients. In a
study of 32,225 diabetic and non-diabetic patients, the rate of finding of any myopathic event
was 7.9% for statin use vs. 5.5% for non-statin use among diabetics, and 9.0% vs. 3.7% for
non-diabetics
[12]
and one other observational PRIMO (Prediction of Muscular Risk in
Observational Conditions) study of 7924 French patients exposed to high-dose statins found
that 10.5% had muscle-related symptoms over 12 months [15].Identification of the
mechanisms causing skeletal myopathy is needful as it may lead to the development of
effective preventive measures or treatments for patients who would benefit from statin
therapy. There are number of hypothesis by which statin may affect the muscle function i.e.
disturbing Ca++[4,5], or ATP synthesis and release[5], disturbing mitochondrial functioning[5],
Cl- conductance[6,7] etc. One more participant, that is Vitamin-D, as statin and Vitamin-D
both affect skeletal muscle metabolism and Vitamin-D deficiency increase the statin
1
associated skeletal muscle complaints, so, vitamin-D may be one participant in statin
associated myopathy[8,9]. Current evidence, however, indicate that depletion of isoprenoids
and regulatory protein levels, such as farensyl pyrophosphate (FPP) and geranylgeranyl
pyrophosphate (GGPP) derivatives, are likely determinants of myotoxicity in vitro[10] and
also modifies the proteomic profile of rat skeletal muscle after chronic treatment[11]. As
statin-induced apoptosis of healthy skeletal myocytes, may be a contributing factor causing
myopathy.[13, 14].
Different Mechanisms of statin related myalgia
1. Impaired calcium signaling
Alteration of structures involved in Ca++ homeostasis could play a pivotal role in producing
myocyte injury. After 2 to 3 months of chronic treatment of rats with simvastatin, the voltage
threshold for contraction (mechanical threshold, MT), a calcium- sensitive index of
excitation-contraction coupling, was shifted toward more negative potentials in fast-twitch
muscle fibers, an effect that is compatible with an increase of resting cytosolic calcium
concentration ([Ca++]i)[5] .
In preclinical studies, 5 mg/kg/day fluvastatin or atorvastatin produced a significant increase
in [Ca++]i, with a concomitant decrease of the caffeine responsiveness and no changes in
sarcolemmal calcium permeability. So, this findings clearly indicate that capability of drug to
alter calcium homeostasis is by interfering with intracellular targets involved with calcium
handling mechanisms [4,5].
Both, in vivo and in vitro statin-treated fibers, the amplitude of the fluvastatin-induced
increase of [Ca++]i did not vary after withdrawal of extracellular calcium, thus strongly
indicating that the drug effect on resting [Ca++]i is not due to an increase of the sarcolemmal
cationic permeability but rather to an internal [Ca++]i store depletion. And higher dose 20
mg/kg/day also showed compromised sarcomere organization and a significant decrease of
the depolarization-induced intracellular calcium peak. It might be possible that, at this high
drug dosage together with the disruption of calcium homeostasis, a series of other cellular
mechanisms may take place, all events accounting for the described detrimental effects like
an alteration of the T-tubule membrane composition, breakdown of the T-tubular system and
by subsarcolemmal ruptures [39] etc.
2
2. Effect of statin on Cl- conductance
Chloride channels play an important role in skeletal muscles by their contribution in
controlling resting membrane potential (gCl-) and membrane repolarization. A large gCl-,
carried by the ClC-1 chloride channel, is important for muscle function as it stabilizes resting
membrane potential (RMP) and helps to repolarize the membrane after action potentials [29].
Loss of function mutations in ClC-1 cause myotonia, congenita, an inherited condition
characterized by delayed skeletal muscle relaxation after voluntary contraction [30]. Chronic
treatment of rabbit by simvastatin has been shown to trigger a membrane hyper excitability
similar to that observed during muscle myotonies associated with impaired chloride
conductance [31]. Figure. B
Resting gCl- strictly depends on ClC-1 chloride channel expression and regulation play
important role in controlling resting gCl-. ClC-1 channel function is down regulated by Ca++
and phospholipid-dependent protein kinase C (PKC) [32,33]. Accordingly, recent studies
confirmed that statins either chronically administered or applied acutely in vitro produce a
mitochondria-mediated increase of resting cytosolic calcium in intact muscle cells [4]. Due to
high resting cytosolic calcium there is activation of PKC enzyme which leads to higher
phophorylation and closure of a fraction of ClC-1 channels [34]. In one preclinical study,
chelerythrine; a PKC inhibitor, significantly increased gCl- of muscles from atorvastatintreated rat by 40%, reaching the value measured in control rats [35]. One preclinical study
reported reduce expression of mRNA which transcript the CLC-1 protein. So, PKC over
activation may lead to reduced gCl- and so hyper excitability of the muscle.
3. Apoptosis and statin induced myopathy
Statin shown to induce apoptosis in skeletal myoblasts, myotyubes, and in differentiated
primary human skeletal muscle cell as similar to the other cell types in concentration
dependent manner [40,43]. Statins translocates the Bax to the mitochondria and statin also
found to decrease expression of the Bcl-2 in the vascular muscle, which may lead to decrease
in the Bcl-2/Bax ratio leading to cytochrome c release and activation of caspase-9, followed
by activation of caspase-3, a mitochondria mediated apoptotic signaling pathway [40, 42].
Figure.A.
3
Remedies for statin related myalgia
Statins competitively inhibit 3-HMGCoA reductase, the rate-limiting step in cholesterol
biosynthesis that catalyses the conversion of 3-HMGCoA to mevalonate metabolites,
including
geranylgeranylpyrophosphate
(GGPP),
farnesylpyrophosphate
(FPP),
and
coenzyme Q10. Inhibition of one of this metabolite leads to myalgia [16].
Mevalonate metabolite synthesis inhibition and myopathy
Statins competitively inhibit 3-HMGCoA reducates, the rate-limiting step in cholesterol
biosynthesis that catalyses the conversion of 3-HMGCoA to mevalonate metabolites,
including
geranylgeranylpyrophosphate
(GGPP),
farnesylpyrophosphate
(FPP),
and
coenzyme Q10. Inhibition of one of this metabolite leads to myalgia [16].
1. Coenzyme Q10
Among these all mevalonate metabolites, Coenzyme Q10 is widely studied as numbers of
preclinical and clinical studies were completed and numbers of studies are going on. As,
coenzyme Q10 participates in electron transport during oxidative phosphorylation in
mitochondria, protects against oxidative stress produced by free radicals [17] and also
regenerates active forms of the antioxidants ascorbic acid and tocopherol (vitamin E) [18, 19]
. Statin inhibit the synthesis of it and found to reduces plasma and muscle CoQ10 level
[20,21] and clinical evidences also show that CoQ10 oral supplement leads to rise in plasma
Coenzyme Q10 level and reduce myalgia pain score [22] . This is somewhat controversial as
one another study shows increased plasma Coenzyme Q10 level and not reduced myalgia
score and not muscle Coenzyme Q10 concentration is raised [21,23] So. It is controversial
whether CoQ10 has role in statin related myopathy or not and further great work is required
with it to established its role in statin related myalgia.
2. Fernasyl pyrophophate (FPP) and Granylgeranyl pyrophosphate (GGPP)
Both FPP and GGPP are synthesized through mevalonate pathway, and participate in number
of physiological function of cell either directly or indirectly. Number of preclinical studies
were carried out in recent to find out the role of them in statin related myopathy [24,25].
4
GGPP is required for various GTPase activation [24] and as geranylgeranylpyrophosphate
(GGPP) supplement inhibit the Fluvastatin (Flv) and pravastatin induced vacuolar
degeneration and cell death in cultured single Skeletal myofibers from rat flexor digitorum
brevis (FDB) muscles [25], we can say that there is some role of GGPP in statin related
myopathy. There are two geranylgeranyltransferases (GG transferases): One is GG
transferase-I, which mediates geranylgeranylation of small GTPases except Rab, including
Rho, Rac, and Cdc. The other is Rab GG transferase (also called GG transferase- II), which
prenylates exclusively Rab GTPases.
Perillyl alcohol (POH), is inhibitor of both Rab GG transferase and GG transferase-I, but it is
twice as potent in inhibiting Rab GG transferase as GG transferase-I [11]. GGTI-298 is a
specific inhibitor of GG transferase-I [26]. As only POH induced morphological changes
similar to Flv, but not GGTI-298 [25]. So, it indicate that inactivation of Rab was responsible
for the Flv effects of vacuolation and cell death in myofibers.
It had been reported that one of the most susceptible isoforms to GGPP depletion was Rab1,
which is essential for vesicular transport from the endoplasmic reticulum (ER) to the Golgi
apparatus (ER-to-Golgi traffic) [27]. Recently Syoko et al. found in myofibers that Rab1 was
inactivated by Flv and that the effect of Flv was reproduced by brefeldin A (BFA), a specific
inhibitor of ER-to-Golgi traffic [24]. These results suggested that depletion of GGPP and
subsequent inactivation of Rab1 lead to inhibition of ER-to-Golgi membrane traffic and this
is one of the main causes of statin-induced vacuolation and cell death in the skeletal
myofibers [28].
As GGPP inhibit the Flv induced Ca++ release from the sarcoplasmic reticulum (SR) in
myofibers which is one of the possible mechanism for muscle contraction, but this is not
inhibited by FPP supplements and since ATP is essential for muscle contraction, amount of
ATP is decreased in Flv-treated myofibers in which contraction is suppressed also inhibited
by GGPP and not by FPP [24]. So, GGPP depletion may be one of the factor for statin related
myalgia and required vigorous in vivo preclinical and clinical study to established the role of
it in the statin related myalgia.
5
Vitamin-D
Vitamin D is produced endogenously from cholesterol via 7-DHC and so Statins reduce both
cholesterol and 7-DHC production, and would be expected to reduce vitamin D production.
Several clinical anecdotes [44,45], case reports [46,47], and two cross-sectional studies
[48,49] have linked vitamin D deficiency with statin myopathy. Among 11 patients with
statin myalgia prompting statin discontinuation, 8 were vitamin D insufficient (25(OH) D<
60 nmol/L (24.04 ng/mL) and 3 of these were severely deficient (25(OH) D< 30 nmol/L
(12.02 ng/mL). 6 of the 8 patients had complete resolution and 2 had significant
improvement of myalgia over approximately 3 months with cessation of the statin and
vitamin D replacement (1000–10,000 units/day) with a target >60 nmol/L, (24.04 ng/mL). 4
of the 6 patients agreed to re-challenged with the same statin after vitamin D repletion and
tolerated statin therapy for at least 6 months without myalgia. In 2 patients, the statin dose
was successfully up titrated to achieve target lipid levels. The 3 vitamin D sufficient patients
were not re-challenged with the same statin, but did tolerate pravastatin. These results
suggest an association between vitamin D deficiency and statin myopathy and that correcting
vitamin D deficiency allows an adequate statin dose to achieve target lipid levels. However,
such case collections depend on subjective reports of myalgia, lack placebo controls, and
cannot be used to determine definitely a causal association
[46]
. However, recently in a large
cohort study of statin treated patients with stable CHD treated with atorvastatin, vitamin D
serum levels were not associated with incidence of myalgia.
Discussion
As we discussed all the probable way by which statin might be affect the skeletal muscle and
produce myopathy. However, it is very difficult to determine by which mechanism statin
produced myalgia. It is possible that one or more probable mechanism simultaneously
participates and produced muscle related problem with statin used. Statin might be first affect
the intracellular ca++ by interfering with intracellular ca++ resources, which may lead to
activation of the apoptic enzymes and so, which leads to apoptosis in muscle cells. However,
as it inhibit 3-HMGCoA enzyme and deplete the GGPP, which is required to activate the
specific GTP transferase-1, Rab, which is required for the ER-to-Golgi membrane traffic
control and this is one of the main causes of statin-induced vacuolation and cell death in the
6
skeletal myofibers. As statin also found to reduced the Cl- conductance which is important
for muscle function as it stabilizes resting membrane potential (RMP) and helps to repolarize
the membrane after action potentials as it found to over activates PKC, due to high [Ca++]i
which down regulate the CLC-1 channel, and also inhibit the expression of mRNA required
for CLC-1 channel.
Conclusion
The geranygeranylpyrophosphate shows to inhibit the statin induced muscle damage in
preclinical study. However, till date not a single clinical study is going on or completed. So ,
if it will studied then it might be one of the remedies for the statin related myalgia and patient
benefited with statin treatment without myalgia.
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12
Table 1: Proposed Definitions for Statin-Related Myopathy
Clinical Entity
Myopathy
ACC/AHA/NHLBI
NLA
FDA
Any disease of muscles
Symptoms of myalgia (muscle pain
Creatine
or soreness),weakness, or cramps,
kinase
with creatine kinase >10× ULN (17–
× ULN
≥10
148 U/L in male, 10 – 79 U/L in
female)
Myalgia
Muscle
weakness
ache
or Not defined
Not defined
without
creatine kinase elevation
Myositis
Muscle symptoms with NA
NA
creatine kinase elevation
[ACC -American College of Cardiology, AHA - American Heart Association, NHLBI National Heart, Lung, and Blood Institute; FDA - U.S. Food and Drug Administration; NA not available; NLA - National Lipid Association; ULN - upper limit of normal.]
13
Fig.A
Fig.B
14
15