Muscle phenotype of AGAT- and GAMT-deficient mice after simvastatin exposure
| Autor: | Ricarda Grzybowski, Erik Hanff, Rainer H. Böger, D. Tsikas, Kathrin Cordts, Christian Gerloff, Axel Neu, Ali Sasani, Chi-Un Choe, Dirk Isbrandt, Sönke Hornig, Edzard Schwedhelm |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Simvastatin metabolism [Muscle Skeletal] Clinical Biochemistry drug effects [Gene Expression Regulation] Biochemistry metabolism [Homoarginine] chemistry.chemical_compound Mice Myocyte pharmacology [Simvastatin] DNA Modification Methylases antagonists & inhibitors [DNA Repair Enzymes] genetics [DNA Repair Enzymes] drug effects [Muscle Skeletal] Guanidinoacetate N-methyltransferase Phenotype ddc:540 genetics [Guanidinoacetate N-Methyltransferase] Animal studies antagonists & inhibitors [DNA Modification Methylases] medicine.symptom medicine.drug Genetically modified mouse medicine.medical_specialty Statin medicine.drug_class metabolism [Arginine] Arginine Creatine 03 medical and health sciences genetics [Tumor Suppressor Proteins] Internal medicine antagonists & inhibitors [Tumor Suppressor Proteins] medicine Animals Humans Muscle Skeletal Myopathy metabolism [Creatine] 030102 biochemistry & molecular biology business.industry Tumor Suppressor Proteins Organic Chemistry genetics [DNA Modification Methylases] nutritional and metabolic diseases Homoarginine DNA Repair Enzymes 030104 developmental biology Endocrinology Gene Expression Regulation chemistry deficiency [Guanidinoacetate N-Methyltransferase] Guanidinoacetate N-Methyltransferase business |
| Zdroj: | Amino acids 52(1), 73-85 (2019). doi:10.1007/s00726-019-02812-4 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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