Mechanisms of statin-associated skeletal muscle-associated symptoms

Bouitbir, Jamal; Sanvee, Gerda M.; Panajatovic, Miljenko V.; Singh, François; Krähenbühl, Stephan

doi:10.1016/j.phrs.2019.03.010

Cited by 97 publications

(117 citation statements)

References 132 publications

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“…We have shown in a previous study that atorvastatin can induce a shift from an oxidative to a glycolytic fibre type in skeletal muscle of mice . We considered this fibre shift to be one of the reasons for statin‐induced myotoxicity, since glycolytic fibres have less antioxidative capacity and are more vulnerable to statins . On the other hand, as stated above, muscle‐specific overexpression of PGC‐1α in mice leads to a shift from glycolytic to oxidative fibres .…”

Section: Discussionmentioning

confidence: 93%

“…Our knowledge about the mechanisms of statin induced skeletal muscle injury is currently incomplete . Several studies have suggested that mitochondria may play a role in statin‐induced myotoxicity.…”

Section: Introductionmentioning

confidence: 99%

“…By inhibiting the synthesis of mevalonate, statins impair the production of coenzyme Q, which is an important constituent of the electron transport chain . Coenzyme Q deficiency may therefore be a cause for mitochondrial toxicity of statins, but its contribution to myotoxicity of statins is debated . In addition, several studies have shown that statins can inhibit the function of the electron transport chain directly by inhibiting the function of enzyme complexes of the respiratory chain .…”

Section: Introductionmentioning

confidence: 99%

“…Our knowledge about the mechanisms of statin induced skeletal muscle injury is currently incomplete. 4 Several studies have suggested that mitochondria may play a role in statin-induced myotoxicity. By inhibiting the synthesis of mevalonate, statins impair the production of coenzyme Q, which is an important constituent of the electron transport chain.…”

mentioning

confidence: 99%

“…5 Coenzyme Q deficiency may therefore be a cause for mitochondrial toxicity of statins, but its contribution to myotoxicity of statins is debated. 4,6 In addition, several studies have shown that statins can inhibit the function of the electron transport chain directly by inhibiting the function of enzyme complexes of the respiratory chain. 3,[7][8][9] Mitochondria not only produce energy in the form of ATP, but are also important generators of reactive oxygen species (ROS), which can act either as a second messenger or as a source of cellular damage, depending on the amount of ROS being produced.…”

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confidence: 99%

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PGC‐1α plays a pivotal role in simvastatin‐induced exercise impairment in mice

et al. 2019

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Aim Statins decrease cardiovascular complications, but can induce myopathy. Here, we explored the implication of PGC‐1α in statin‐associated myotoxicity. Methods We treated PGC‐1α knockout (KO), PGC‐1α overexpression (OE) and wild‐type (WT) mice orally with 5 mg simvastatin kg−1 day−1 for 3 weeks and assessed muscle function and metabolism. Results In WT and KO mice, but not in OE mice, simvastatin decreased grip strength, maximal running distance and vertical power assessed by ergometry. Post‐exercise plasma lactate concentrations were higher in WT and KO compared to OE mice. In glycolytic gastrocnemius, simvastatin decreased mitochondrial respiration, increased mitochondrial ROS production and free radical leak in WT and KO, but not in OE mice. Simvastatin increased mRNA expression of Sod1 and Sod2 in glycolytic and oxidative gastrocnemius of WT, but decreased it in KO mice. OE mice had a higher mitochondrial DNA content in both gastrocnemius than WT or KO mice and simvastatin exhibited a trend to decrease the citrate synthase activity in white and red gastrocnemius in all treatment groups. Simvastatin showed a trend to decrease the mitochondrial volume fraction in both muscle types of all treatment groups. Mitochondria were smaller in WT and KO compared to OE mice and simvastatin further reduced the mitochondrial size in WT and KO mice, but not in OE mice. Conclusions Simvastatin impairs skeletal muscle function, muscle oxidative metabolism and mitochondrial morphology preferentially in WT and KO mice, whereas OE mice appear to be protected, suggesting a role of PGC‐1α in preventing simvastatin‐associated myotoxicity.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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PGC‐1α plays a pivotal role in simvastatin‐induced exercise impairment in mice

et al. 2019

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Synergistic interaction between B vitamins and statins to counter nociception in rats

López-Canales

Estefania

Carolina

et al. 2020

Drug Development Research

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Evidence suggests that the antinociceptive activity of various drugs can be increased when administered in combination with B vitamins (BVs). The aim of this study was to examine the potential interaction between statins and BVs to counter nociception, the latter measured by the formalin test. Rats were orally administered atorvastatin (1, 3, 10 and 30 mg/kg), pravastatin (1, 3, 10 and 30 mg/kg), rosuvastatin (1, 3, 10 and 30 mg/kg), BVs (31, 56, 100 and 180 mg/kg) or calculated combinations of BVs with each drug. The effective dose 30 (ED30) was calculated for each statin and BVs and subjected to isobolographic analysis, thus finding the ED30 of the combinations. The antinociceptive experimental ED30 values for BVs administered with atorvastatin, pravastatin or rosuvastatin were 1.53 ± 0.38, 6.74 ± 0.04 and 4.26 ± 0.39, respectively, being lower (p < .05) than the corresponding theoretical ED30: 28.02 ± 2.20, 28.17 ± 2.20 and 29.86 ± 2.21. Since BVs likely boost the antinociceptive effect of statins, these combinations could possibly be advantageous in pain management.

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Atorvastatin and pravastatin stimulate nitric oxide and reactive oxygen species generation, affect mitochondrial network architecture and elevate nicotinamide N‐methyltransferase level in endothelial cells

Dymkowska

Wrzosek

Zabłocki

2020

J of Applied Toxicology

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Statins belong to the most often prescribed medications, which efficiently normalise hyperlipidaemia and prevent cardiovascular complications in obese and diabetic patients. However, beside expected therapeutic results based on the inhibition of 3‐hydroxyl‐3‐methylglutaryl‐CoA reductase, these drugs exert multiple side effects of poorly understood characteristic. In this study, side effects of pravastatin and atorvastatin on EA.hy926 endothelial cell line were investigated. It was found that both statins activate proinflammatory response, elevate nitric oxide and reactive oxygen species (ROS) generation and stimulate antioxidative response in these cells. Moreover, only slight stimulation of the mitochondrial biogenesis and significant changes in the mitochondrial network organisation have been noted. Although biochemical bases behind these effects are not clear, they may partially be explained as an elevation of AMP‐activated protein kinase (AMPK) activity and an increased activating phosphorylation of sirtuin 1 (Sirt1), which were observed in statins‐treated cells. In addition, both statins increased nicotinamide N‐methyltransferase (NNMT) protein level that may explain a reduced fraction of methylated histone H3. Interestingly, a substantial reduction of the total level of histone H3 in cells treated with pravastatin but not atorvastatin was also observed. These results indicate a potential additional biochemical target for statins related to reduced histone H3 methylation due to increased NNMT protein level. Thus, NNMT may directly modify gene activity.

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Mechanisms of statin-associated skeletal muscle-associated symptoms

Cited by 97 publications

References 132 publications

PGC‐1α plays a pivotal role in simvastatin‐induced exercise impairment in mice

PGC‐1α plays a pivotal role in simvastatin‐induced exercise impairment in mice

Synergistic interaction between B vitamins and statins to counter nociception in rats

Atorvastatin and pravastatin stimulate nitric oxide and reactive oxygen species generation, affect mitochondrial network architecture and elevate nicotinamide N‐methyltransferase level in endothelial cells

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