Statin and fibrate associed myopathy: study of eight patients

Carvalho, Aline Martins de; Lima, Úrsula Waleska Poti; Valiente, Raul Alberto

doi:10.1590/s0004-282x2004000200013

Cited by 28 publications

(14 citation statements)

References 14 publications

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“…Low intracellular cholesterol levels modulate fluidity of cell membranes. This in turn alters in the Na+/k+ pump function leads to degeneration of the membranous organelles of muscle fibers [28]. Sirvent et al, 2005 [29] reported that simvastatin induces an efflux of Ca2+ from the mitochondria of isolated human muscle fibers.…”

Section: The Morphometric Resultsmentioning

confidence: 99%

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

Mokhmer¹,

Saber²,

Hamouda³

et al. 2017

J Cytol Histol

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Section: The Morphometric Resultsmentioning

confidence: 99%

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

Mokhmer¹,

Saber²,

Hamouda³

et al. 2017

J Cytol Histol

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“…Simvastatin‐related mitochondrial dysfunction resulted in skeletal muscle injury that manifested as increased plasma CK and centronucleated muscle fibres. Thus, simvastatin was able to enhance reactive oxygen species (ROS) generation and muscle fibre necrosis, which indicates that the muscular adverse reaction of simvastatin is related to mitochondrial dysfunction …”

Section: Discussionmentioning

confidence: 99%

Trimetazidine restores the positive adaptation to exercise training by mitigating statin‐induced skeletal muscle injury

Song

Chen

et al. 2017

J cachexia sarcopenia muscle

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BackgroundExercise rehabilitation is demonstrated to improve the prognosis of patients with coronary heart disease (CHD). Statins, as the key medicine to lower cholesterol in CHD, result in skeletal muscle injury and impair exercise training adaptation. Energy metabolism dysfunction is identified as the potential mechanism underlying statin‐induced skeletal muscle injury. In this study, we investigated the effects of the metabolic modulator trimetazidine on skeletal muscle energy metabolism and statin‐associated exercise intolerance.MethodsHigh‐fat fed apolipoprotein E knockout (ApoE−/−) mice were given aerobic exercise and administrated simvastatin, trimetazidine, or simvastatin plus trimetazidine by gavage. Exercise capacity was evaluated at the end of the treatment by hanging grid test, forelimb grip strength, and running tolerance test. Plasma glucose, lipid, and creatine kinase concentrations were measured at the end of the treatment. After sacrifice, gastrocnemii were stored for assessment of muscle morphology and fibre type. Energy metabolism was estimated by plasma lactic acid concentration, ragged red fibres, and glycogen stores. Activities of mitochondrial complex III, citrate synthase activity, and membrane potential were measured to assess mitochondrial function. Oxidative stress was also evaluated by superoxide in mitochondria, superoxide dismutase activity, and glutathione redox state.ResultsIn high‐fat fed ApoE−/− mice, exercise training had no effect on lipid concentrations. Lower lipid concentrations with increased creatine kinase were observed with additional simvastatin treatment. Exercise capacity increased significantly in response to exercise training alone but was blunted by the addition of simvastatin. Similarly, cross‐sectional area of muscle fibres and the proportion of slow‐twitch fibres increased in the exercise group but decreased in the simvastatin plus exercise group. Additionally, simvastatin increased centronucleated fibres and induced energy metabolism dysfunction by inhibiting complex III activity and thus promoted oxidative stress in gastrocnemius. We demonstrated that trimetazidine could reverse simvastatin‐induced exercise intolerance and muscle damages. We also found the ability of trimetazidine in restoration of muscle fibre hypertrophy and facilitating fast‐to‐slow type shift. The energy metabolism dysfunction and oxidative stress in gastrocnemii were rescued by trimetazidine.ConclusionsTrimetazidine alleviated statin‐related skeletal muscle injury by restoration of oxidative phenotype and increasing fibre cross‐sectional areas in response to exercise training. Correspondingly, the exercise training adaptation were improved in high‐fat fed ApoE−/− mice. Moreover, trimetazidine is able to exert its positive effects without affecting the beneficial lipid‐lowering properties of the statins. Thus, trimetazidine could be prescribed to remedy the undesirable statins‐induced exercise intolerance during cardiac rehabilitation in patients with CHD.

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“…These results suggest that other mechanisms, besides inhibition of HMG-CoA reductase, play a role in the repressive effects during differentiation of myoblasts. Elevation of serum CK activity in statin-associated myopathy is responsible for acute muscle fiber necrosis with leakage of muscle constituents into blood (Carvalho et al, 2004). Our C2C12 cells were seeded in 6-well culture plates at 10 4 cells/cm 2 and preincubated in GM for 24 hr.…”

Section: Discussionmentioning

confidence: 99%

SIMVASTATIN REDUCES INSULIN-LIKE GROWTH FACTOR-1 SIGNALING IN DIFFERENTIATING C2C12 MOUSE MYOBLAST CELLS IN AN HMG-CoA REDUCTASE INHIBITION-INDEPENDENT MANNER

Ogura¹,

Tanaka²,

Nakata³

et al. 2007

J. Toxicol. Sci.

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-Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase occasionally cause myopathy characterized by weakness, pain, and elevated serum creatine phosphokinase (CK). In this study, we investigated the effects of simvastatin, an HMG-CoA reductase inhibitor, on the viability and insulin-like growth factor-1 (IGF-1) signaling in differentiating C2C12 mouse myoblast cells. Simvastatin decreased cell viability and CK activity, a marker of myogenesis, in differentiating cells in a dosedependent manner. Although the simvastatin-induced decrease in viability in proliferating and differentiated cells was completely abolished by mevalonate or geranylgeranyl-pyrophosphate, the inhibitory effects of simvastatin in differentiating cells were not abolished by mevalonate or isoprenoid derivatives of mevalonate. Moreover, the sensitivity of differentiating cells to simvastatin regarding cell viability was about 7 times higher than that of proliferating cells. After induction of differentiation in the presence of 1 μM simvastatin for 2 days, IGF-1-induced activation of ERK1/2 and Akt was significantly decreased. Although mRNA expression of the IGF-1 receptor β-chain (IGF-1Rβ) did not change, protein level of the 200 kDa IGF-1Rβ precursor was significantly increased by simvastatin in a dose-dependent manner. Mevalonate did not abolish the effect of simvastatin on IGF-1Rβ expression. These results suggest that simvastatin decreases IGF-1 signaling via a regulation of the post-translational modification of IGF-1Rβ in an HMG-CoA reductase inhibition-independent manner.

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Statin and fibrate associed myopathy: study of eight patients

Cited by 28 publications

References 14 publications

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

Trimetazidine restores the positive adaptation to exercise training by mitigating statin‐induced skeletal muscle injury

SIMVASTATIN REDUCES INSULIN-LIKE GROWTH FACTOR-1 SIGNALING IN DIFFERENTIATING C2C12 MOUSE MYOBLAST CELLS IN AN HMG-CoA REDUCTASE INHIBITION-INDEPENDENT MANNER

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