Cell Metabolism
Previews Does Reduced Creatine Synthesis Protect against Statin Myopathy? Kevin D. Ballard1 and Paul D. Thompson1,* 1Division of Cardiology, Henry Low Heart Center, Hartford Hospital, Hartford, CT 06102, USA *Correspondence: [email protected] http://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 reduced creatine production protects against statin myopathy remains to be determined. Hydroxy-methyl-glutaryl Co-A (HMG CoA) reductase inhibitors or ‘‘statins’’ inhibit mevalonate production, ultimately reducing low-density lipoprotein (LDL) cholesterol concentrations and cardiovascular 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 these muscle complaints are produced by the same mechanism, but this is not certain and at least one muscle side effect, an autoimmune myositis (muscle inflammation), is associated 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 highdose 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 important issue. Numerous possible genetic variants 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 associated with reduced hepatic statin uptake 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 statin myopathy, although these variants, in CYP3A4/5, 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 coenzyme Q10 (CoQ10) production pathway, have also been proposed to affect statin myalgia. CoQ10 is a mitochondrial electron transport protein that is also produced by the mevalonate pathway. Reductions in CoQ10 production could adversely affect cellular energy production. These are only three of multiple possible genetic variants affecting statin myopathy (Ghatak et al., 2010). Mangravite and colleagues (Mangravite et al., 2013) are the first to identify creatine biosynthesis as another possible contributor to statin myopathy. Creatine, or methylguanidine acetic acid, is synthesized predominantly in the liver and kidneys by a two-reaction pathway utilizing glycine, arginine, and methionine. Creatine is then transported to skeletal muscle where it combines with inorganic phosphate to form creatine phosphate (CP).
CP is rapidly split by CK to produce creatine 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) used a genomewide expression quantitative trait loci (eQTL) analysis in lymphoblastoid cell lines (LCLs) from 480 middle-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. Simvastatin 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 synthesis. Furthermore, the relationship between the GATM differential eQTL locus expression with simvastatin exposure and statin-induced myopathy was examined in two separate population-based cohorts comprising 172 cases of myopathy (Link et al., 2008; Mareedu et al., 2009). Calculation of an odds ratio to quantify the association between presence 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 cohorts, suggesting that reduced GATM expression, and probable reduced creatine synthesis, is associated with a reduced incidence of statin-induced myopathy. Collectively, these data are the first to identify a genetic variant
Cell Metabolism 18, December 3, 2013 ª2013 Elsevier Inc. 773
Cell Metabolism
Previews
regulating creatine synthesis statin-induced myopathy are and highlight reduced intraintriguing but require addimuscular creatine as a potentional study to determine their tial protector against statinsignificance. induced muscle problems. REFERENCES The authors propose that simvastatin reduced GATM Edvardson, S., Korman, S.H., Livne, expression in rs9806699 carA., Shaag, A., Saada, A., Nalbanriers, reducing creatine availdian, R., Allouche-Arnon, H., Gomori, J.M., and Katz-Brull, R. ability and CP storage. They (2010). Mol. Genet. Metab. 101, speculate that reduced CP 228–232. storage modifies skeletal Ghatak, A., Faheem, O., and muscle cellular energy pathThompson, P.D. (2010). Atheroscleways leading to reduced susrosis 210, 337–343. ceptibility to statin myopathy Link, E., Parish, S., Armitage, J., (Figure 1). Bowman, L., Heath, S., Matsuda, F., Gut, I., Lathrop, M., and Collins, R.; This is a unique hypothSEARCH Collaborative Group esis, but questions remain. (2008). N. Engl. J. Med. 359, 789–799. Figure 1. Proposed Mechanism by which Reduced GATM Activity No prior studies, including Reduces Statin Myopathy Risk Mangravite, L.M., Engelhardt, B.E., several genome-wide associSimvastatin reduced GATM transcriptional expression, and this effect was Medina, M.W., Smith, J.D., Brown, associated with a reduced incidence of statin myopathy (Mangravite et al., ation studies (GWAS) (Link C.D., Chasman, D.I., Mecham, 2013). Reduced intramuscular Cr may protect against statin-induced myopet al., 2008; Ruan˜o et al., B.H., Howie, B., Shim, H., Naidoo, athy. GATM, glycine amidinotransferase; CP, creatine phosphate; Cr, creatine. D., et al. (2013). Nature 502, 2011), have identified the 377–380. GATM gene as a contributor to statin myopathy. In the study by Man- contrast to the authors’ hypothesis (Man- Mareedu, R.K., Modhia, F.M., Kanin, E.I., LinneJ.G., Kitchner, T., McCarty, C.A., Krauss, gravite et al. (2013), statin myopathy in gravite et al., 2013), GATM deficiency man, R.M., and Wilke, R.A. (2009). Prev. Cardiol. 12, their cohorts was defined by CK elevations was associated with a myopathy in two 88–94. three to ten times the upper-normal limits siblings that improved with oral creatine Mohassel, P., and Mammen, A.L. (2013). Muscle (Link et al., 2008; Mareedu et al., 2009). treatment (Edvardson et al., 2010), sug- Nerve 48, 477–483. But perhaps the rs9806699 variant re- gesting that depleting intramuscular Parker, B.A., Capizzi, J.A., Grimaldi, A.S., Clarkduces both myocyte creatine and CK creatine does not protect against, but son, P.M., Cole, S.M., Keadle, J., Chipkin, S., levels so that any skeletal muscle injury causes, myopathy. Over-the-counter cre- Pescatello, L.S., Simpson, K., White, C.M., produces less CK elevation and fewer atine supplementation actually appeared and Thompson, P.D. (2013). Circulation 127, 96–103. diagnoses of statin myopathy. Arguing to reduce statin-associated muscle comagainst this possibility is the observation plaints in ten patients with statin myalgia, Ruan˜o, G., Windemuth, A., Wu, A.H., Kane, J.P., Malloy, M.J., Pullinger, C.R., Kocherla, M., that plasma CK levels measured before but these data (Shewmon and Craig, Bogaard, K., Gordon, B.R., Holford, T.R., et al. and after statin treatment were not associ- 2010) warrant investigation in a much (2011). Atherosclerosis 218, 451–456. ated with the GATM variant in subjects larger cohort. Shewmon, D.A., and Craig, J.M. (2010). Ann. In summary, these data (Mangravite Intern. Med. 153, 690–692. without myopathy (Mangravite et al., 2013), but this does not address the possi- et al., 2013) identifying a statin-responsive Voora, D., Shah, S.H., Spasojevic, I., Ali, S., Reed, bility that intramuscular CK levels are genetic variant in GATM expression C.R., Salisbury, B.A., and Ginsburg, G.S. (2009). related to the GATM genotype. Also, in associated with reduced susceptibility to J. Am. Coll. Cardiol. 54, 1609–1616.
774 Cell Metabolism 18, December 3, 2013 ª2013 Elsevier Inc.
Previews Does Reduced Creatine Synthesis Protect against Statin Myopathy? Kevin D. Ballard1 and Paul D. Thompson1,* 1Division of Cardiology, Henry Low Heart Center, Hartford Hospital, Hartford, CT 06102, USA *Correspondence: [email protected] http://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 reduced creatine production protects against statin myopathy remains to be determined. Hydroxy-methyl-glutaryl Co-A (HMG CoA) reductase inhibitors or ‘‘statins’’ inhibit mevalonate production, ultimately reducing low-density lipoprotein (LDL) cholesterol concentrations and cardiovascular 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 these muscle complaints are produced by the same mechanism, but this is not certain and at least one muscle side effect, an autoimmune myositis (muscle inflammation), is associated 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 highdose 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 important issue. Numerous possible genetic variants 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 associated with reduced hepatic statin uptake 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 statin myopathy, although these variants, in CYP3A4/5, 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 coenzyme Q10 (CoQ10) production pathway, have also been proposed to affect statin myalgia. CoQ10 is a mitochondrial electron transport protein that is also produced by the mevalonate pathway. Reductions in CoQ10 production could adversely affect cellular energy production. These are only three of multiple possible genetic variants affecting statin myopathy (Ghatak et al., 2010). Mangravite and colleagues (Mangravite et al., 2013) are the first to identify creatine biosynthesis as another possible contributor to statin myopathy. Creatine, or methylguanidine acetic acid, is synthesized predominantly in the liver and kidneys by a two-reaction pathway utilizing glycine, arginine, and methionine. Creatine is then transported to skeletal muscle where it combines with inorganic phosphate to form creatine phosphate (CP).
CP is rapidly split by CK to produce creatine 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) used a genomewide expression quantitative trait loci (eQTL) analysis in lymphoblastoid cell lines (LCLs) from 480 middle-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. Simvastatin 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 synthesis. Furthermore, the relationship between the GATM differential eQTL locus expression with simvastatin exposure and statin-induced myopathy was examined in two separate population-based cohorts comprising 172 cases of myopathy (Link et al., 2008; Mareedu et al., 2009). Calculation of an odds ratio to quantify the association between presence 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 cohorts, suggesting that reduced GATM expression, and probable reduced creatine synthesis, is associated with a reduced incidence of statin-induced myopathy. Collectively, these data are the first to identify a genetic variant
Cell Metabolism 18, December 3, 2013 ª2013 Elsevier Inc. 773
Cell Metabolism
Previews
regulating creatine synthesis statin-induced myopathy are and highlight reduced intraintriguing but require addimuscular creatine as a potentional study to determine their tial protector against statinsignificance. induced muscle problems. REFERENCES The authors propose that simvastatin reduced GATM Edvardson, S., Korman, S.H., Livne, expression in rs9806699 carA., Shaag, A., Saada, A., Nalbanriers, reducing creatine availdian, R., Allouche-Arnon, H., Gomori, J.M., and Katz-Brull, R. ability and CP storage. They (2010). Mol. Genet. Metab. 101, speculate that reduced CP 228–232. storage modifies skeletal Ghatak, A., Faheem, O., and muscle cellular energy pathThompson, P.D. (2010). Atheroscleways leading to reduced susrosis 210, 337–343. ceptibility to statin myopathy Link, E., Parish, S., Armitage, J., (Figure 1). Bowman, L., Heath, S., Matsuda, F., Gut, I., Lathrop, M., and Collins, R.; This is a unique hypothSEARCH Collaborative Group esis, but questions remain. (2008). N. Engl. J. Med. 359, 789–799. Figure 1. Proposed Mechanism by which Reduced GATM Activity No prior studies, including Reduces Statin Myopathy Risk Mangravite, L.M., Engelhardt, B.E., several genome-wide associSimvastatin reduced GATM transcriptional expression, and this effect was Medina, M.W., Smith, J.D., Brown, associated with a reduced incidence of statin myopathy (Mangravite et al., ation studies (GWAS) (Link C.D., Chasman, D.I., Mecham, 2013). Reduced intramuscular Cr may protect against statin-induced myopet al., 2008; Ruan˜o et al., B.H., Howie, B., Shim, H., Naidoo, athy. GATM, glycine amidinotransferase; CP, creatine phosphate; Cr, creatine. D., et al. (2013). Nature 502, 2011), have identified the 377–380. GATM gene as a contributor to statin myopathy. In the study by Man- contrast to the authors’ hypothesis (Man- Mareedu, R.K., Modhia, F.M., Kanin, E.I., LinneJ.G., Kitchner, T., McCarty, C.A., Krauss, gravite et al. (2013), statin myopathy in gravite et al., 2013), GATM deficiency man, R.M., and Wilke, R.A. (2009). Prev. Cardiol. 12, their cohorts was defined by CK elevations was associated with a myopathy in two 88–94. three to ten times the upper-normal limits siblings that improved with oral creatine Mohassel, P., and Mammen, A.L. (2013). Muscle (Link et al., 2008; Mareedu et al., 2009). treatment (Edvardson et al., 2010), sug- Nerve 48, 477–483. But perhaps the rs9806699 variant re- gesting that depleting intramuscular Parker, B.A., Capizzi, J.A., Grimaldi, A.S., Clarkduces both myocyte creatine and CK creatine does not protect against, but son, P.M., Cole, S.M., Keadle, J., Chipkin, S., levels so that any skeletal muscle injury causes, myopathy. Over-the-counter cre- Pescatello, L.S., Simpson, K., White, C.M., produces less CK elevation and fewer atine supplementation actually appeared and Thompson, P.D. (2013). Circulation 127, 96–103. diagnoses of statin myopathy. Arguing to reduce statin-associated muscle comagainst this possibility is the observation plaints in ten patients with statin myalgia, Ruan˜o, G., Windemuth, A., Wu, A.H., Kane, J.P., Malloy, M.J., Pullinger, C.R., Kocherla, M., that plasma CK levels measured before but these data (Shewmon and Craig, Bogaard, K., Gordon, B.R., Holford, T.R., et al. and after statin treatment were not associ- 2010) warrant investigation in a much (2011). Atherosclerosis 218, 451–456. ated with the GATM variant in subjects larger cohort. Shewmon, D.A., and Craig, J.M. (2010). Ann. In summary, these data (Mangravite Intern. Med. 153, 690–692. without myopathy (Mangravite et al., 2013), but this does not address the possi- et al., 2013) identifying a statin-responsive Voora, D., Shah, S.H., Spasojevic, I., Ali, S., Reed, bility that intramuscular CK levels are genetic variant in GATM expression C.R., Salisbury, B.A., and Ginsburg, G.S. (2009). related to the GATM genotype. Also, in associated with reduced susceptibility to J. Am. Coll. Cardiol. 54, 1609–1616.
774 Cell Metabolism 18, December 3, 2013 ª2013 Elsevier Inc.
