Cell Metabolism

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Does Reduced Creatine SynthesisProtect against Statin Myopathy?

Kevin D. Ballard1 and Paul D. Thompson1,*1Division of Cardiology, Henry Low Heart Center, Hartford Hospital, Hartford, CT 06102, USA*Correspondence: paul.thompson@hhchealth.orghttp://dx.doi.org/10.1016/j.cmet.2013.11.012

Statins, widely used to lower cholesterol levels, cause myopathy in some patients. Mangravite et al. (2013)show that a single nucleotide polymorphism decreasing expression of glycine amidinotransferase (GATM),the enzyme regulating creatine biosynthesis, is associated with reduced statin myopathy. Whether reducedcreatine production protects against statin myopathy remains to be determined.

Hydroxy-methyl-glutaryl Co-A (HMGCoA)

reductase inhibitors or ‘‘statins’’ inhibit

mevalonate production, ultimately re-

ducing low-density lipoprotein (LDL)

cholesterol concentrations and cardiovas-

cular morbidity and mortality. Statins are

extremely well tolerated but can produce

skeletal muscle adverse effects in some

patients, ranging from myalgia (muscle

pain), cramps, weakness, and stiffness to

markedly elevated creatine kinase (CK)

levels, indicating skeletal muscle damage

and rhabdomyolysis (muscle breakdown).

It is assumed that all of thesemuscle com-

plaints are produced by the same mecha-

nism, but this is not certain and at least

one muscle side effect, an autoimmune

myositis (muscle inflammation), is associ-

ated with antibodies against HMG CoA

reductase (Mohassel and Mammen,

2013). Statin-induced rhabdomyolysis

and autoimmune myositis are extremely

rare, but the STOMP (Effect of Statins on

Muscle Performance) study (Parker et al.,

2013) reported that treatment with high-

dose atorvastatin, one of the most

commonly prescribed statins, doubled

the incidence of myalgia compared with

placebo from 4.6% to 9.4%, suggesting

that the overall incidence of statin myalgia

is approximately 5%. Statins are among

the most widely prescribed medicines

worldwide, making prediction of who can

and cannot tolerate these drugs an impor-

tant issue.Numerouspossible genetic var-

iants affecting statin myopathy have been

identified (Ghatak et al., 2010). Mangravite

and colleagues (Mangravite et al., 2013)

now identify a variant in the gene for

glycine amidinotransferase (GATM), the

rate-limiting enzyme required for creatine

biosynthesis, as a possible genetic

contributor to statin myopathy.

The findings of Mangravite et al. add

to the growing list of genetic variants

associated with statin-related muscle

complaints. These include the gene for

the organic anion transporter, SLCO1B1.

The SLCO1B1 *5 variant (rs4149056) is

associatedwith reduced hepatic statin up-

take and increased myalgia (Voora et al.,

2009) and rhabdomyolysis (Link et al.,

2008), suggesting that reduced hepatic

uptake increases the amount of statin

that survives hepatic passage and can

enter skeletal muscle. Variants in genes in

the cytochrome P enzyme system (CYP),

which catabolize statins, may also affect

the frequency of statinmyopathy,although

these variants, inCYP3A4/5,CYP2D6, and

CYP2C9, appear most important when

statins are combined with other drugs

metabolized by the same CYP enzyme

(Ghatak et al., 2010). Variants in the

COQ2 gene, a component of the coen-

zyme Q10 (CoQ10) production pathway,

have also been proposed to affect statin

myalgia. CoQ10 is a mitochondrial elec-

tron transport protein that is alsoproduced

by themevalonate pathway.Reductions in

CoQ10 production could adversely affect

cellular energy production. These are

only three of multiple possible genetic var-

iants affecting statin myopathy (Ghatak

et al., 2010).

Mangravite and colleagues (Mangravite

et al., 2013) are the first to identify creatine

biosynthesis as another possible contrib-

utor to statin myopathy. Creatine, or

methylguanidine acetic acid, is synthe-

sized predominantly in the liver and kid-

neys by a two-reaction pathway utilizing

glycine, arginine, and methionine. Crea-

tine is then transported to skeletal muscle

where it combines with inorganic phos-

phate to form creatine phosphate (CP).

Cell Metabolism 18,

CP is rapidly split by CK to produce crea-

tine and inorganic phosphate. The latter

combines with ADP to form ATP. CP

thus serves as an important cellular

energy source for rapid resynthesis of

ATP to meet the energy demands of

intense activities.

Mangravite et al. (2013) useda genome-

wide expression quantitative trait loci

(eQTL) analysis in lymphoblastoid cell

lines (LCLs) from480middle-aged healthy

volunteers from a simvastatin treatment

trial. LCLs, which are a common model

system to screen for genetic variants,

were exposed to simvastatin or control

buffer for 24 hr. Six eQTL were identified

that interact with simvastatin exposure.

These included a single nucleotide

polymorphism rs9806699 in GATM. Sim-

vastatin exposure produced a 2-fold

greater reduction in GATM expression in

cells from rs9806699 carriers than in

cells from noncarriers. Reduced GATM

expression should reduce creatine syn-

thesis. Furthermore, the relationship be-

tween the GATM differential eQTL locus

expression with simvastatin exposure

and statin-induced myopathy was exam-

ined in two separate population-based

cohorts comprising 172 cases of myop-

athy (Link et al., 2008; Mareedu et al.,

2009). Calculation of an odds ratio to

quantify the association between pres-

ence of the rs9806699 variant and statin

myopathy resulted in an overall odds ratio

of 0.60 (95% confidence interval = 0.45–

0.81) with meta-analysis of these two co-

horts, suggesting that reduced GATM

expression, and probable reduced crea-

tine synthesis, is associated with a

reduced incidence of statin-induced

myopathy. Collectively, these data are

the first to identify a genetic variant

December 3, 2013 ª2013 Elsevier Inc. 773

Figure 1. Proposed Mechanism by which Reduced GATM ActivityReduces Statin Myopathy RiskSimvastatin reduced GATM transcriptional expression, and this effect wasassociated with a reduced incidence of statin myopathy (Mangravite et al.,2013). Reduced intramuscular Cr may protect against statin-induced myop-athy. GATM, glycine amidinotransferase; CP, creatine phosphate; Cr, creatine.

Cell Metabolism

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regulating creatine synthesis

and highlight reduced intra-

muscular creatine as a poten-

tial protector against statin-

induced muscle problems.

The authors propose that

simvastatin reduced GATM

expression in rs9806699 car-

riers, reducing creatine avail-

ability and CP storage. They

speculate that reduced CP

storage modifies skeletal

muscle cellular energy path-

ways leading to reduced sus-

ceptibility to statin myopathy

(Figure 1).

This is a unique hypoth-

esis, but questions remain.

No prior studies, including

several genome-wide associ-

ation studies (GWAS) (Link

et al., 2008; Ruano et al.,

2011), have identified the

GATM gene as a contributor

to statin myopathy. In the study by Man-

gravite et al. (2013), statin myopathy in

their cohortswasdefinedbyCKelevations

three to ten times the upper-normal limits

(Link et al., 2008; Mareedu et al., 2009).

But perhaps the rs9806699 variant re-

duces both myocyte creatine and CK

levels so that any skeletal muscle injury

produces less CK elevation and fewer

diagnoses of statin myopathy. Arguing

against this possibility is the observation

that plasma CK levels measured before

and after statin treatmentwere not associ-

ated with the GATM variant in subjects

without myopathy (Mangravite et al.,

2013), but this does not address the possi-

bility that intramuscular CK levels are

related to the GATM genotype. Also, in

774 Cell Metabolism 18, December 3, 2013 ª

contrast to the authors’ hypothesis (Man-

gravite et al., 2013), GATM deficiency

was associated with a myopathy in two

siblings that improved with oral creatine

treatment (Edvardson et al., 2010), sug-

gesting that depleting intramuscular

creatine does not protect against, but

causes, myopathy. Over-the-counter cre-

atine supplementation actually appeared

to reduce statin-associated muscle com-

plaints in ten patients with statin myalgia,

but these data (Shewmon and Craig,

2010) warrant investigation in a much

larger cohort.

In summary, these data (Mangravite

et al., 2013) identifying a statin-responsive

genetic variant in GATM expression

associated with reduced susceptibility to

2013 Elsevier Inc.

statin-induced myopathy are

intriguing but require addi-

tional study to determine their

significance.

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