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Cited by 165Coenzyme Q10 studies and effectsMitochondrial Function and PathologyLipoproteins and Cardiovascular Health

Simvastatin Effects on Skeletal Muscle

Open access
Larsen, Steen, Stride, Nis, Hey-Mogensen, Martin, Hansen, Christina N., Bang, Lia E., Bundgaard, Henning, Nielsen, Lars B., Helge, Jørn W. +1 more·2013·Journal of the American College of Cardiology
DOI 10.1016/j.jacc.2012.09.036
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Abstract

Objectives Glucose tolerance and skeletal muscle coenzyme Q(10) (Q(10)) content, mitochondrial density, and mitochondrial oxidative phosphorylation (OXPHOS) capacity were measured in simvastatin-treated patients (n = 10) and in well-matched control subjects (n = 9).Background A prevalent side effect of statin therapy is muscle pain, and yet the basic mechanism behind it remains unknown. We hypothesize that a statin-induced reduction in muscle Q(10) may attenuate mitochondrial OXPHOS capacity, which may be an underlying mechanism.Methods Plasma glucose and insulin concentrations were measured during an oral glucose tolerance test. Mitochondrial OXPHOS capacity was measured in permeabilized muscle fibers by high-resolution respirometry in a cross-sectional design. Mitochondrial content (estimated by citrate synthase [CS] activity, cardiolipin content, and voltage-dependent anion channel [VDAC] content) as well as Q(10) content was determined.Results Simvastatin-treated patients had an impaired glucose tolerance and displayed a decreased insulin sensitivity index. Regarding mitochondrial studies, Q(10) content was reduced (p = 0.05), whereas mitochondrial content was similar between the groups. OXPHOS capacity was comparable between groups when complex I- and complex II-linked substrates were used alone, but when complex I + II-linked substrates were used (eliciting convergent electron input into the Q intersection [maximal ex vivo OXPHOS capacity]), a decreased (p < 0.01) capacity was observed in the patients compared with the control subjects.Conclusions These simvastatin-treated patients were glucose intolerant. A decreased Q(10) content was accompanied by a decreased maximal OXPHOS capacity in the simvastatin-treated patients. It is plausible that this finding partly explains the muscle pain and exercise intolerance that many patients experience with their statin treatment.

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Written from the paper’s full text.

TL;DR

In a cross-sectional study of 10 simvastatin-treated hypercholesterolemic men and 9 matched controls, simvastatin treatment was associated with impaired glucose tolerance, reduced skeletal muscle Q10 content, and reduced maximal mitochondrial OXPHOS capacity when complex I+II substrates were combined. These findings suggest a possible mechanism for statin-associated muscle pain and exercise intolerance.

Key findings

  • Patients had impaired glucose tolerance and lower insulin sensitivity: Cederholm index 33 [29–40] vs 56 [44–92] (p≤0.05); glucose was higher during the OGTT (p<0.05), while insulin levels were similar.
  • Skeletal muscle Q10 protein content was reduced (0.84±0.15 vs 1.00±0.18 AU, p=0.05); catalase, MnSOD, glutathione peroxidase, and UCP3 were also reduced, and complex IV content was lower (p<0.05), whereas CS activity, VDAC, and cardiolipin content were similar.
  • Maximal OXPHOS capacity with complex I+II-linked substrates was lower in patients (54±8 vs 64±10 pmol/mg/s, p<0.01), while complex I alone (24±8 vs 26±6 pmol/mg/s), complex II, and complex IV capacities did not differ; maximal OXPHOS correlated weakly with Q10 content (r=0.46, p<0.05).
  • Complex I substrate sensitivity was higher in patients (lower C50: 0.98±0.23 vs 1.37±0.51 mmol/l, p<0.05), with no difference for succinate; 4/10 patients reported muscle pain vs 0/9 controls (VAS 2±2 vs 0±0, p≤0.05), and CK levels were comparable.

Methods

  • Cross-sectional study: 20 male subjects recruited—10 hypercholesterolemic patients on simvastatin 10–40 mg/day for at least 12 months (average 5 years) and 10 healthy controls; one control was omitted after impaired glucose tolerance was found, leaving n=10 patients and n=9 controls. Groups were matched for age, weight, BMI, fat percentage, and VO2max.
  • A 2-h OGTT measured glucose and insulin and calculated the Cederholm insulin sensitivity index; DXA and incremental cycling determined body composition and VO2max; muscle biopsies were obtained from m. vastus lateralis. Permeabilized fibers were analyzed by high-resolution respirometry using five substrate/inhibitor protocols, alongside Western blots, enzyme activities, and lipid quantification.
  • Statistics used repeated-measures 2-way ANOVA with Holm-Sidak post hoc tests, 1-way ANOVA or nonparametric tests as appropriate, and Pearson correlations; p<0.05 was considered significant.

Limitations

  • Stated in the paper: the mechanism for reduced glucose tolerance is unknown and speculative; the Q10–maximal OXPHOS correlation was weak and requires confirmation; ROS production was not measured; the role of intramyocellular lipids in insulin resistance remains unresolved.
  • Evident from the text: small sample (n=10 patients, n=9 controls), male-only, cross-sectional design without randomization or placebo; medication was not withdrawn; groups differed in muscle fiber type composition and some clinical variables (e.g., systolic BP, HbA1c, VAS), which may confound findings.

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Registry

Crossref · 10.1016/j.jacc.2012.09.036

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 46 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Skeletal muscle free cholesterol did not differ between groups.

    “Skeletal muscle free cholesterol was similar in the 2 groups (Table 2).”
    Quote in the paperNot a substantial claim
  • Findingown data

    A weak positive correlation was found between maximal OXPHOS capacity (complex I+II-linked) and Q10 content (r=0.46, p<0.05).

    “A weak positive correlation (r ϭ 0.46, p Ͻ 0.05) was observed between maximal OXPHOS capacity (complex I ϩ II-linked substrates) and Q 10 content.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Skeletal muscle Q10 protein content was lower in simvastatin-treated patients than in controls (p=0.05).

    “Q 10 content was reduced (p ϭ 0.05), whereas mitochondrial content was similar between the groups.”
    • Also stated in: § Results · plain
      “Q 10 protein content was reduced (p ϭ 0.05) in patients compared with control subjects (Table 2).”
    • Also stated in: § Discussion · plain
      “Furthermore, a decrease is found in Q 10 protein content in skeletal muscle, accompanied by a limitation in maximal OXPHOS capacity in the patients treated with simvastatin.”
    Quote in the paperSubstantial claim
  • Findingown data

    Substrate sensitivity with succinate (complex II-linked) did not differ between groups.

    “When succinate (complex II-linked substrate) was used as a substrate, no differences were seen in OXPHOS capacity (Fig. 3) or in substrate sensitivity (Fig. 5B) between the groups.”
    Quote in the paperNot a substantial claim
  • Findingown data

    A non-significant trend suggested a dose effect: patients on 40 mg/day simvastatin had higher glutamate substrate sensitivity than those on 10-20 mg/day and controls (p=0.076).

    “A tendency (p ϭ 0.076) for a drug dose effect was seen in substrate sensitivity when glutamate was used as substrate; the patients that were treated with 40 mg of simvastatin per day (n ϭ 5) had a higher mitochondrial substrate sensitivity (complex I-linked substrate) compared with patients treated with 10 to 20 mg of simvastatin per day (n ϭ 5) and with the control subjects (0.84 Ϯ 0.06 mmol/l vs”
    Quote in the paperNot a substantial claim
  • May combine two claims. 26
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    Simvastatin-treated patients showed impaired glucose tolerance compared with controls, with higher OGTT glucose and increased glucose AUC.

    “Simvastatin-treated patients had an impaired glucose tolerance and displayed a decreased insulin sensitivity index.”
    • Also stated in: § Results · plain
      “During the OGTT, glucose concentration was significantly higher (p Ͻ 0.05) in patients compared with controls, resulting in an increased (p Ͻ 0.05) area under the glucose curve in the simvastatintreated patients (Fig. 2).”
    • Also stated in: § Discussion · boosted
      “A major and novel finding is the impaired glucose tolerance found in the patients in treatment with simvastatin, which was shown by a simple OGTT.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HAD activity and HAD protein content tended to be lower in patients than controls (p=0.06 and p=0.07).

    “A tendency (p ϭ 0.06) towards lower HAD activity was seen in patients compared with control subjects (Table 2); the same was seen in HAD protein content (p ϭ 0.07) in patients compared with control subjects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Complex IV protein content was lower in patients, complex V tended lower, and complex I-III content was similar between groups.

    “Complex IV content was significantly reduced (p Ͻ 0.05), whereas complex V showed a tendency (p ϭ 0.07) to be reduced in patients compared with control subjects, but complex I to III protein content was similar between the groups (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Fasting plasma glucose and insulin did not differ between the two groups.

    “Fasting plasma glucose and insulin concentrations were comparable between groups (Fig. 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Antioxidant proteins (catalase, MnSOD, glutathione peroxidase) and UCP3 were lower in patients than controls.

    “The antioxidant (catalase [p Ͻ 0.05], MnSOD [p Ͻ 0.01], and glutathione peroxidase [p Ͻ 0.05]) as well as UCP3 (p Ͻ 0.01) protein content was significantly reduced in patients compared with control subjects (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Four of ten simvastatin-treated patients reported muscle pain, while no controls did.

    “Four of the 10 patients reported muscle pain, whereas none of the controls did (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There is a correlation between Q10 content and maximal OXPHOS capacity, though it is not strong.

    “supported by the correlation between Q 10 content and maximal OXPHOS capacity, even though this correlation was not strong and has to be confirmed in other studies.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The differences observed between simvastatin-treated patients and control subjects are attributable to simvastatin treatment rather than to hypercholesterolemia or other baseline differences.

  • May combine two claims.

    Findingreasoning

    Skeletal muscle from simvastatin-treated patients had increased mitochondrial substrate sensitivity (lower C50) with complex I-linked substrate glutamate compared with controls, but no difference with complex II-linked substrate succinate.

    “Skeletal muscle from simvastatin-treated patients had increased mitochondrial substrate sensitivity (lower C 50 value) with complex I-linked substrate (glutamate) compared with muscle from the control subjects, but no difference was seen with complex II-linked substrate (succinate).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The differences observed between simvastatin-treated patients and control subjects are attributable to simvastatin treatment rather than to hypercholesterolemia or other baseline differences.

  • May combine two claims.

    Study design and conductown data

    No cytochrome c response occurred in any protocol, indicating intact outer mitochondrial membrane after the procedure.

    “No cytochrome c response was observed in any of the protocols (data not shown), implying that the outer mitochondrial membrane was intact after the experimental procedure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The patient and control groups were matched for age, weight, BMI, total and abdominal fat percentage, and VO2max.

    “The groups were matched for age, weight, body mass index, fat percentage (total and abdominal), and maximal oxygen uptake (VO 2MAX ) (Table 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    One control subject was found to have impaired glucose tolerance and was excluded, leaving nine controls.

    “After the subjects were recruited and the blood and skeletal muscle were analyzed, 1 of the control subjects turned out to have impaired glucose tolerance; therefore, data from this subject were omitted, leaving 9 in the control group.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Subjects with a family history of type 2 diabetes were excluded.

    “Subjects with a family history of type 2 diabetes were excluded from the study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The Ohrvall et al. study was conducted in patients with type 2 diabetes, which may confound its results.

    “The latter study was performed in patients with type 2 diabetes, which could be a confounding factor.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Ohrvall, 1995, A comparison between the effects of gemfibrozil and simvastatin on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus and hyperlipoproteinemia, Metabolism source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A prior study's groups were not matched for VO2max, which is problematic because exercise training strongly stimulates mitochondrial biogenesis and unmeasured mitochondrial content differences would affect respiration results.

    “However, the study groups were not matched for maximal oxygen uptake (physical fitness), which is problematic because exercise training is the most powerful stimulus for mitochondrial biogenesis (18), and differences in mitochondrial content (which was not measured in the study [17]) would have had a major influence on the respiratory results.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Holloszy, 2008, Regulation by exercise of skeletal muscle content of mitochondria and GLUT4, J Physiol Pharmacol

      Not checked in the free run.

    • cites [17] Sirvent, 2012, Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins, Toxicol Appl Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High-dose simvastatin (80 mg/day) has been reported to decrease muscle Q10 protein content, while lower doses (20 mg/day) have not shown this decrease.

    “Other studies with high simvastatin doses (80 mg/day) have reported decreased Q 10 protein content in muscle from simvastatin-treated patients (12,13), whereas studies using lower (20 mg/day) doses have been unable to demonstrate decreased muscle Q 10 protein content (14,15)”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [12] Paiva, 2005, High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial, Clin Pharmacol Ther source

      Not checked in the free run.

    • cites [13] Schick, 2007, Decreased skeletal muscle mitochondrial DNA in patients treated with high-dose simvastatin, Clin Pharmacol Ther source

      Not checked in the free run.

    • cites [14] Laaksonen, 1996, The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle, Am J Cardiol source

      Not checked in the free run.

    • cites [15] Laaksonen, 1995, Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans, Clin Pharmacol Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Statins reduce cholesterol formation via the mevalonate pathway, and this pathway may also affect mitochondrial coenzyme Q10 formation.

    “Statins act via the mevalonate pathway to reduce the formation of cholesterol, but impingement of this pathway may also affect the formation of the mitochondrial cofactor, coenzyme Q 10 (Q 10 ) (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Hargreaves, 2005, The effect of HMG-CoA reductase inhibitors on coenzyme Q10: possible biochemical/clinical implications, Drug Saf source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Control and statin samples were loaded alternately to avoid transfer efficiency variation.

    “Control and statin-treated subjects were loaded in an alternating pattern to avoid regional variation in transfer efficiency.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Respiratory measurements were performed in duplicate after hyperoxygenation to prevent oxygen limitation.

    “Briefly, all respiratory measurements were carried out in duplicate after hyperoxygenation to avoid any potential oxygen limitation to respiration.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Kwak et al. reported impaired ADP-stimulated respiration in primary human skeletal myotubes after 48 h of simvastatin treatment, accompanied by increased mitochondrial oxidative stress.

    “Recently Kwak et al. (40) reported impaired ADP-stimulated respiration in primary human skeletal myotubes after 48 h of simvastatin treatment, and this was accompanied by increased mitochondrial oxidative stress (hydrogen peroxide emission).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Kwak, 2012, Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes, Free Radic Biol Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The Cederholm index of peripheral insulin sensitivity has been validated against the hyperinsulinemic-euglycemic clamp.

    “Glucose and insulin concentrations during the OGTT were used to calculate the Cederholm index of peripheral insulin sensitivity (32), which has been validated against the hyperinsulinemic-euglycemic clamp (33).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Cederholm, 1990, Insulin release and peripheral sensitivity at the oral glucose tolerance test, Diabetes Res Clin Pract source

      Not checked in the free run.

    • cites [33] Pigeon, 2009, Validation of a simple index (SIisOGTT) of insulin sensitivity in a population of sedentary men, Diabetes Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute statin effects have been studied in isolated mitochondria from L6 cells and skinned human and rat muscle, where simvastatin showed a toxic effect and depressed complex I respiration.

    “The acute effect of statins has, however, been studied in isolated mitochondria from L6 cells (a rat skeletal muscle cell line) (39) and in skinned human and rat muscle (16) in which a toxic effect of simvastatin and depressed complex I respiration was found.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [39] Kaufmann, 2006, Toxicity of statins on rat skeletal muscle mitochondria, Cell Mol Life Sci source

      Not checked in the free run.

    • cites [16] Sirvent, 2005, Simvastatin induces impairment in skeletal muscle while heart is protected, Biochem Biophys Res Commun source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Normality and equal variance assumptions were checked before statistical testing.

    “The restrictive assumptions, normality and equal variance, were checked before the statistical analysis was conducted.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Cytochrome c was added to test outer mitochondrial membrane integrity.

    “then cytochrome c (10 mol/l) was added to control for outer mitochondrial membrane integrity.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    UCP3 has been suggested to protect mitochondria against accumulation of nonesterified fatty acids.

    “UCP3 has been suggested to protect the mitochondria against an accumulation of nonesterified fatty acids (35)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Schrauwen, 2001, An alternative function for human uncoupling protein 3: protection of mitochondria against accumulation of nonesterified fatty acids inside the mitochondrial matrix, FASEB J source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The mechanism behind statin-induced myopathic changes is not fully understood.

    “Adverse effects of statin treatment on skeletal muscle (from myositis to rhabdomyolysis) have been reported, but the mechanism behind these myopathic changes is not fully understood (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Thompson, 2003, Statin-associated myopathy, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prior work found that simvastatin-treated hypercholesterolemic patients had lower skeletal muscle Q10 and mitochondrial content, but only with lipophilic simvastatin.

    “In hypercholesterolemic patients treated with simvastatin, the content of Q 10 in skeletal muscle was reduced, and this was paralleled by a reduction in mitochondrial content (estimated by citrate synthase [CS] activity and mitochondrial DNA content), but only when a lipophilic statin was used (simvastatin) (12,13).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Paiva, 2005, High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial, Clin Pharmacol Ther source

      Not checked in the free run.

    • cites [13] Schick, 2007, Decreased skeletal muscle mitochondrial DNA in patients treated with high-dose simvastatin, Clin Pharmacol Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A prior study of patients on different statins reported lower complex I OXPHOS capacity and no difference in complex II-linked OXPHOS capacity.

    “Recently, the same group investigated mitochondrial function in patients treated with different statins (lipophilic and hydrophilic) and reported the same results: decreased complex I OXPHOS capacity in the patients and no differences in complex II-linked OXPHOS capacity (17).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Sirvent, 2012, Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins, Toxicol Appl Pharmacol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Protein expression analyses were run twice.

    “Protein expression in simvastatin-treated subjects was measured relative to the mean values of the control group; all analyses were performed twice.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Statin treatment has been reported to impair insulin sensitivity and increase type 2 diabetes prevalence, with lipophilic statins having a stronger effect than hydrophilic statins.

    “Recently, it has been reported that statin treatment impairs insulin sensitivity and increases the prevalence of type 2 diabetes (19 -22); and it seems that lipophilic statins (i.e., simvastatin, atorvastatin, fluvastatin, lovastatin) have a more pronounced effect on insulin sensitivity compared with hydrophilic statins (i.e., pravastatin, rosuvastatin) (23).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [19] Koh, 2009, Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients, Atherosclerosis source

      Not checked in the free run.

    • cites [20] Koh, 2008, Simvastatin improves flow-mediated dilation but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients, Diabetes Care source

      Not checked in the free run.

    • cites [21] Ohrvall, 1995, A comparison between the effects of gemfibrozil and simvastatin on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus and hyperlipoproteinemia, Metabolism source

      Not checked in the free run.

    • cites [22] Koh, 2010, Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients, J Am Coll Cardiol source

      Not checked in the free run.

    • cites [23] Koh, 2011, Differential metabolic effects of distinct statins, Atherosclerosis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute statin treatment was reported to lower complex I-linked OXPHOS capacity in human skeletal muscle without affecting complex II-linked respiration.

    “The acute effect of statin treatment on mitochondrial oxidative phosphorylation (OXPHOS) capacity in human skeletal muscle has been investigated, and a decrease in OXPHOS capacity with complex I-linked substrates was reported, whereas respiration with complex II-linked substrates was unaffected (16).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Sirvent, 2005, Simvastatin induces impairment in skeletal muscle while heart is protected, Biochem Biophys Res Commun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prior studies by Koh et al. used the Quantitative Insulin-Sensitivity Check Index as a surrogate measure for insulin sensitivity, while Ohrvall et al. used the hyperinsulinemic-euglycemic clamp technique.

    “The 3 studies by Koh et al. (19,20,22) from 2008, 2009, and 2010 used the Quantitative Insulin-Sensitivity Check Index as a surrogate measure for insulin sensitivity, whereas the study by Ohrvall et al. (21) from 1995 used the hyperinsulinemic-euglycemic clamp technique.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [19] Koh, 2009, Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients, Atherosclerosis source

      Not checked in the free run.

    • cites [20] Koh, 2008, Simvastatin improves flow-mediated dilation but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients, Diabetes Care source

      Not checked in the free run.

    • cites [22] Koh, 2010, Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients, J Am Coll Cardiol source

      Not checked in the free run.

    • cites [21] Ohrvall, 1995, A comparison between the effects of gemfibrozil and simvastatin on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus and hyperlipoproteinemia, Metabolism source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased Ca2+ load in the mitochondrial matrix is linked to increased ROS production and permeability transition pore opening, leading to apoptosis.

    “In turn, an increased Ca 2ϩ load in the mitochondrial matrix has been linked to increased ROS production and increased permeability transition pore opening, leading to apoptosis (40,45).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] Kwak, 2012, Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes, Free Radic Biol Med source

      Not checked in the free run.

    • cites [45] Brookes, 2004, Calcium, ATP, and ROS: a mitochondrial love-hate triangle, Am J Physiol Cell Physiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    The increased mitochondrial substrate sensitivity could be a compensatory mechanism for increased ROS production.

    “we hypothesize that this could be a compensatory mechanism for increased ROS production.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The mitochondrial membrane potential is mainly created by the activity of complexes I, III, and IV, and compromised function of one or more of these may lower it.

  • Classified as probably not a substantial claim.

    Premisecitation

    VDAC in the outer mitochondrial membrane is important for Ca2+ in- and outflux of mitochondria.

    “It has been reported that VDAC located in the outer mitochondrial membrane is important for the in-and outflux of Ca 2ϩ of the mitochondria (43)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Gincel, 2001, Calcium binding and translocation by the voltage-dependent anion channel: a possible regulatory mechanism in mitochondrial function, Biochem J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Other studies have shown increased ROS production and decreased antioxidant capacity with statin treatment.

    “other studies have shown increased ROS production (3,42) and a decreased antioxidant capacity (3) with statin treatment.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Bouitbir, 2012, Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a ‘mitohormesis’ mechanism involving reactive oxygen species and PGC-1, Eur Heart J source

      Not checked in the free run.

    • cites [42] Bouitbir, 2011, Atorvastatin treatment reduces exercise capacities in rats: involvement of mitochondrial impairments and oxidative stress, J Appl Physiol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The result is a compromised energetic state in skeletal muscle, possibly explaining side effects such as myalgia and exercise intolerance.

    “The result is a compromised energetic state within the skeletal muscle, possibly explaining side effects such as myalgia and exercise intolerance.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Ex vivo measurements of mitochondrial function reflect in vivo mitochondrial function and can explain clinical symptoms such as exercise intolerance and myalgia.

  • May combine two claims.

    Interpretationreasoning

    The difference in complex I-linked substrate sensitivity between simvastatin-treated patients and controls is a true intrinsic mitochondrial event, because the C50 parameter is independent of mitochondrial density.

    “The difference between simvastatin-treated patients and the control subjects in complex I-linked substrate sensitivity is a true intrinsic event in the mitochondrion, because the derived sensitivity parameter (C 50 ) of the titration studies is independent of mitochondrial density.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The C50 parameter derived from titration studies is independent of mitochondrial density.
37 of 37

  • The paper relies on this without support.

    There is a lack of studies on skeletal muscle mitochondrial function in hypercholesterolemic patients on long-term statins.

    “There is a paucity of studies of skeletal muscle mitochondrial function in hypercholesterolemic patients in long-term treatment with statins.”

  • The paper relies on this without support.

    Mitochondrial dysfunction can cause muscle pain and exercise intolerance in statin-treated patients.

    “It is plausible that this finding partly explains the muscle pain and exercise intolerance that many patients experience with their statin treatment.”

  • The paper relies on this without support.

    The differences observed between simvastatin-treated patients and control subjects are attributable to simvastatin treatment rather than to hypercholesterolemia or other baseline differences.

    “patients treated with simvastatin have impaired glucose tolerance compared with healthy control subjects.”

  • The paper relies on this without support.

    The C50 parameter derived from titration studies is independent of mitochondrial density.

    “because the derived sensitivity parameter (C 50 ) of the titration studies is independent of mitochondrial density.”

  • The paper relies on this without support.

    The mitochondrial membrane potential is mainly created by the activity of complexes I, III, and IV, and compromised function of one or more of these may lower it.

    “The membrane potential is mainly created by virtue of the activity of complexes I, III, and IV, and a compromised function of 1 or more of these may lower the membrane potential.”

  • The paper relies on this without support.

    Ex vivo measurements of mitochondrial function reflect in vivo mitochondrial function and can explain clinical symptoms such as exercise intolerance and myalgia.

    “It may be anticipated that the OXPHOS limitation observed ex vivo in the present study serves as a mechanism for the impaired exercise tolerance and fatigability seen in some patients using statins.”

  • The paper relies on this without support.

    No prior studies have combined measurement of a key mitochondrial respiratory chain protein with a functional high-resolution respirometry mitochondrial test.

    “no studies have so far combined this measurement of a key protein in the mitochondrial respiratory chain with a functional (high-resolution respirometry) mitochondrial test.”
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Authors
Larsen, S., Stride, N., Hey-Mogensen, M., Hansen, C. N., Bang, L. E., Bundgaard, H., Nielsen, L. B., Helge, J. W., & Dela, F.
Affiliations
University of Copenhagen (DK)
Corresponding author
Larsen, Steen
ORCID
Venue
Journal of the American College of Cardiology
Publisher
Elsevier BV
Published
2013-01
Volume
61
Issue
1
Pages
44-53
ISSN
0735-1097 (ISSN-L)
DOI
10.1016/j.jacc.2012.09.036
OpenAlex
W2216733834
Semantic Scholar
ce3b2fcd9c516ba54a665dd7f9b31fafef2299f0
Cited by
165
References
47
Citations by year
2026: 3 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 11 · 2020: 12 · 2019: 14 · 2018: 20 · 2017: 13 · 2016: 17 · 2015: 19 · 2014: 21 · 2013: 10
FWCI
6.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American College of Cardiology (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
Danish Council for Independent Research-Medical Sciences (271-07-0271)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
simvastatin, statin-induced myopathy, skeletal muscle, coenzyme Q10, mitochondrial oxidative phosphorylation, mitochondrial density, impaired glucose tolerance, insulin resistance, mitochondrial complex I, succinate dehydrogenase, citrate synthase, cardiolipin, voltage-dependent anion channel, exercise intolerance
MeSH terms
Blood Glucose, Electron Transport, Glucose Tolerance Test, Humans, Insulin Resistance, Male, Middle Aged, Mitochondria, Muscle, Oxidative Phosphorylation, Ubiquinone, Case-Control Studies, Glucose Intolerance, Muscle, Skeletal, Muscle Fibers, Skeletal, Cell Respiration, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Electron Transport Complex II, Electron Transport Complex I

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