Abstract | BACKGROUND: METHODS: LDLr-/- mice were treated with pravastatin for 3, 6 and 10 months. Glucose tolerance, insulin resistance and glucose-stimulated insulin secretion were evaluated. The rates of protein synthesis and degradation were determined in gastrocnemius muscle after 10 months of treatment. Insulin signalling, oxidative stress and cell death were analysed in vitro using C2C12 myotubes. RESULTS: After 6 and 10 months of treatment, these mice became glucose intolerant, and after 10 months, they exhibited marked insulin resistance. Reduced islet glucose-stimulated insulin secretion was observed after the 3rd month of treatment. Mice treated for 10 months showed significantly decreased body weight and increased muscle protein degradation. In addition, muscle chymotrypsin-like proteasomal activity and lysosomal cathepsin were markedly elevated. C2C12 myotubes exposed to increasing concentrations of pravastatin presented dose-dependent impairment of insulin-induced Akt phosphorylation, increased apoptotic markers ( Bax protein and cleaved caspase-3) and augmented superoxide anion production. CONCLUSIONS: In addition to reduced insulin secretion, long-term pravastatin treatment induces insulin resistance and muscle wasting. These results suggest that the diabetogenic effect of statins is linked to the appearance of myotoxicity induced by oxidative stress, impaired insulin signalling, proteolysis and apoptosis.
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Authors | Estela Lorza-Gil, Marta García-Arevalo, Bianca Cristine Favero, Maria Cristina C Gomes-Marcondes, Helena C F Oliveira |
Journal | Journal of translational medicine
(J Transl Med)
Vol. 17
Issue 1
Pg. 285
(08 27 2019)
ISSN: 1479-5876 [Electronic] England |
PMID | 31455371
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Blood Glucose
- Insulin
- Muscle Proteins
- Receptors, LDL
- Superoxides
- Pravastatin
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Topics |
- Animals
- Apoptosis
- Blood Glucose
(metabolism)
- Body Weight
- Cell Line
- Diabetes Mellitus, Experimental
(blood, complications)
- Fasting
(blood)
- Female
- Glucose Intolerance
(blood, complications)
- Homeostasis
- Hypercholesterolemia
(blood, complications)
- Insulin
(blood)
- Insulin Resistance
- Insulin Secretion
- Mice, Inbred C57BL
- Models, Biological
- Muscle Fibers, Skeletal
(metabolism, pathology)
- Muscle Proteins
(metabolism)
- Myotoxicity
(blood, complications)
- Oxidative Stress
- Phosphorylation
- Pravastatin
(adverse effects)
- Proteolysis
- Receptors, LDL
(deficiency, metabolism)
- Signal Transduction
- Superoxides
(metabolism)
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