Muscle phenotype of AGAT- and GAMT-deficient mice after simvastatin exposure

Statin-induced myopathy affects more than 10 million people worldwide. But discontinuation of statin treatment increases mortality and cardiovascular events. Recently, l -arginine:glycine amidinotransferase (AGAT) gene was associated with statin-induced myopathy in two populations, but the causal li...

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Bibliographic Details
Published in:Amino acids 2020-01, Vol.52 (1), p.73-85
Main Authors: Sasani, Ali, Hornig, Sönke, Grzybowski, Ricarda, Cordts, Kathrin, Hanff, Erik, Tsikas, Dimitris, Böger, Rainer, Gerloff, Christian, Isbrandt, Dirk, Neu, Axel, Schwedhelm, Edzard, Choe, Chi-un
Format: Article
Language:English
Subjects:
Analytical Chemistry
Animal models
Arginine
Biochemical Engineering
Biochemistry
Biomedical and Life Sciences
Cardiovascular diseases
Creatine
Glycine
Glycine amidinotransferase
Grip strength
Guanidinoacetate N-methyltransferase
Life Sciences
Methyltransferase
Muscle strength
Myopathy
Neurobiology
Original Article
Patients
Phenotypes
Plasma levels
Proteomics
Rodents
Side effects
Simvastatin
Statins
Supplements
Transgenic mice
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Summary:Statin-induced myopathy affects more than 10 million people worldwide. But discontinuation of statin treatment increases mortality and cardiovascular events. Recently, l -arginine:glycine amidinotransferase (AGAT) gene was associated with statin-induced myopathy in two populations, but the causal link is still unclear. AGAT is responsible for the synthesis of l -homoarginine (hArg) and guanidinoacetate (GAA). GAA is further methylated to creatine (Cr) by guanidinoacetate methyltransferase (GAMT). In cerebrovascular patients treated with statin, lower hArg and GAA plasma concentrations were found than in non-statin patients, indicating suppressed AGAT expression and/or activity ( n  = 272, P  = 0.033 and P  = 0.039, respectively). This observation suggests that statin-induced myopathy may be associated with AGAT expression and/or activity in muscle cells. To address this, we studied simvastatin-induced myopathy in AGAT- and GAMT-deficient mice. We found that simvastatin induced muscle damage and reduced AGAT expression in wildtype mice (myocyte diameter: 34.1 ± 1.3 µm vs 21.5 ± 1.3 µm, P  = 0.026; AGAT expression: 1.0 ± 0.3 vs 0.48 ± 0.05, P  = 0.017). Increasing AGAT expression levels of transgenic mouse models resulted in rising plasma levels of hArg and GAA ( P  
ISSN:0939-4451
1438-2199
DOI:10.1007/s00726-019-02812-4