Statin-induced myopathy in the rat: relationship between systemic exposure, muscle exposure and myopathy

Sidaway, James E.; Wang, Y; Marsden, Alan M.; Orton, Terry C.; Westwood, F. Russell; Azuma, Choka; Scott, Robert C.

doi:10.1080/00498250802585539

Cited by 23 publications

(18 citation statements)

References 43 publications

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“…From day 12 to day 16 there was significant increase in serum ck levels and a variable severity and distribution of muscle fibre necrosis. These results were confirmed by Sidaway et al (17) and Mallinson et al (18). Significant elevation of serum ck and serum myoglobin was also reported by Pierno et al (19), with rats chronically treated with fluvastatin 20 mg/kg b.wt./day and atorvastatin 10 mg/kg b.wt./day for 2 months, and there was no histological sign of muscle damage.…”

Section: Discussionsupporting

confidence: 73%

Influence of Stem Cell Therapy on Statin-induced Myopathy of Skeletal Muscle in Female Rats

...

2012

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Ad dress for Cor res pon den ce/Ya z›fl ma Ad re si:Objective: This is a trial to visualize the role of transplanted bone marrow mesenchymal stem cells (BM-MSCs) in skeletal muscle regeneration after induction of myopathy using a model of statin induced myopathy. Ma te ri al and Met hod: The study was conducted in eighty female and ten male albino rats, male rats for isolation of MSCs and female rats were divided to 8 groups. Group I was administered 0.5% carboxymethyl cellulose (solvent), 25 mg/kg b.w./day, as a control group. Group II was administered simvastatin, 80 mg/kg b.wt./day, for 16 days, then was sacrificed immediately. Group III was administered simvastatin 80 mg/kg b.wt/day, for 16 days, and then the rats were sacrificed 14 days after discontinuing simvastatin. Group IV was administered simvastatin 80 mg/kg b.wt/day for 16 days, then the rats were sacrificed 30 days after discontinuing simvastatin. Group V was administered simvastatin for 30 days, then the rats were sacrificed immediately. Group VI was administered simvastatin for 30 days, with intravenous injection of mesenchymal stem cells on day 16. Group VII was administered simvastatin for 46 days, then the rats were sacrificed immediately. Group VIII was administered simvastatin for 46 days, with intravenous injection of mesenchymal stem cells on day 16. On the morning of the last day of each experimental period needle electromyography (EMG) and nerve conduction (NC) were recorded in gastrocnemius muscle and sciatic nerve. Then rats were sacrificed and blood samples were collected. The gastrocnemius muscles of both limbs were dissected. The right gastrocnemius muscle was processed for histological study and the left one was used for examination of MSCs homing by detection of sry gene using PCR technique. Re sults: Discontinuing simvastatin 14 and 30 days after induction of myopathy caused marked improvement and regeneration of skeletal muscle as manifested by significant improvement in EMG findings. However, there was persistence of mild myopathic changes after simvastatin cessation, indicating partial recovery. MSCs were injected once on day 16. The transplantation of MSC to myopathic rats, with continuous simvastatin administration, induced significant improvement and regeneration. The improvement recorded in EMG 30 days after MSC injection was significantly better than that observed after 14 days. The light microscopic findings were markedly improved within 14 and 30 days after MSC injection. Dis cus si on: MSC injection in myopathic rats induced improvement of skeletal muscle function with pronounced regeneration. (Turkish Journal of Neurology 2012; 18:135-44) Özet Amaç: Bu çalışma, statin ile indüklenen miyopati modeli ile miyopati geliştirilen iskelet kasında, kemik iliği mezenkimal kök hücrelerinin (MKH) kas rejenerasyonundaki etkisini izlemek amacıyla yapılmıştır. Ge reç ve Yön tem: Çalışma 80 dişi ve 10 erkek albino sıçanda yapılmıştır. Erkek sıçanlar mezenkimal kök hücre sağlamak amacı ile kullanılmış, dişi sıçanlar da 8 gruba bölünmü...

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Section: Discussionsupporting

confidence: 73%

Influence of Stem Cell Therapy on Statin-induced Myopathy of Skeletal Muscle in Female Rats

...

2012

Tnd

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Section: Pharmacokinetic and Experimental Datamentioning

confidence: 99%

“…Indeed, one study demonstrated statin concentrations in liver tissue exceeding those in serum, but the difference was only twofold [7]. In contrast, the concentration in brain and muscle tissue is only onethird of that in serum [7,8].The intracellular concentration of statins in endothelial, blood and immunologically active cells is unknown.What statin doses have been used in animal experiments? In humans the dosage of statins varies between approximately 0.1-1 mg kg -1 bodyweight, while most studies in rodents have used doses of 1-100 or even 500 mg kg -1 bodyweight (e.g.…”

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confidence: 99%

What is a relevant statin concentration in cell experiments claiming pleiotropic effects?

Björkhem‐Bergman¹,

Lindh²,

Bergman

2011

Brit J Clinical Pharma

160

143

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Apart from their lipid-lowering effects statins have been ascribed a number of other functions including antiinflammatory and immunomodulatory properties [1]. Notably, most available evidence for the proposed pleiotropic effects of statins is based on in vitro studies.We claim that the results from these in vitro studies are potentially misleading, because of the high statin concentrations used.We performed a systematic literature search identifying in vitro experiments where mechanistic insights behind pleiotropic effects of statins are claimed. Statin concentrations in these cell experiments were compared with concentrations detected in human plasma. We focused on studies published in journals with an impact factor >15, as these reports were likely to have a broad impact on this field of research. Indeed, the choice of statin concentration is frequently based on previous experiments from papers in highimpact journals. In these articles, pleiotropic effects of statins were only detected at statin concentrations of 1-50 mmol L -1

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“…In the present study, we measured the plasma levels of simvastatin in treated mdx mice, which were, on average, 403 ± 108 nM (n = 7). In treated rats, the simvastatin concentration in skeletal muscle relative to plasma is 30% (42). Therefore, we would expect the muscle levels of simvastatin in our mice to be ∼120 nM.…”

Section: Physiological Concentrations Of Simvastatin Do Not Impair Mumentioning

confidence: 99%

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy

Whitehead

Kim

Bible

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

142

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Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to nearnormal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases.statin | muscular dystrophy | fibrosis | inflammation | muscle force D uchenne muscular dystrophy (DMD) is a degenerative muscle disease caused by the absence of dystrophin, a large protein that links the cytoskeleton to the surface membrane in muscle cells. Loss of dystrophin causes widespread effects on muscle signaling and metabolic pathways, leading to cell death and progressive replacement of functional muscle fibers with fibrotic connective tissue. This process results in profound muscle weakness, usually leaving DMD boys wheelchair-bound by their early teenage years and leading to death from the consequences of respiratory and/or cardiac muscle failure by age 20-30. Current treatments, such as corticosteroids, slow disease progression only marginally (1), whereas gene-based approaches, such as exonskipping, although promising in preclinical studies, will need to overcome many technical and regulatory hurdles, as well becoming affordable, before they are a widely available therapy for DMD patients (2). Therefore, efficacious pharmaceutical agents that are cost-effective and already approved for human use are particularly attractive candidates for the current treatment of DM...

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Statin-induced myopathy in the rat: relationship between systemic exposure, muscle exposure and myopathy

Cited by 23 publications

References 43 publications

Influence of Stem Cell Therapy on Statin-induced Myopathy of Skeletal Muscle in Female Rats

Influence of Stem Cell Therapy on Statin-induced Myopathy of Skeletal Muscle in Female Rats

What is a relevant statin concentration in cell experiments claiming pleiotropic effects?

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy

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