Statin exposure during pregnancy promotes neuromuscular junction alterations in postpartum Wistar rats.

INTRODUCTION/AIMS: The mechanisms that underlie the pathogenesis of statin-associated muscle symptoms (SAMS) remain unclear. Pregnancy is associated with increased cholesterol levels. Statins may be useful during pregnancy, but their safety is uncertain. Hence, we investigated the postpartum effects of exposure to rosuvastatin and simvastatin during pregnancy in Wistar rats, targeting the neuromuscular structures. METHODS: Twenty-one pregnant Wistar rats were divided into three groups: control (C) treated with vehicle (dimethylsulfoxide + dH20), simvastatin (S) 62.5 mg/kg/day, and rosuvastatin (R) 10 mg/kg/day. Gavage was performed daily from the gestational days 8 to 20. At weaning, the postpartum mother tissues were collected and subjected to morphological and morphometric analysis of the soleus muscle, associated neuromuscular junctions (NMJs), and the sciatic nerve; protein quantification; quantification of the cholesterol and creatine kinase in the serum; and intramuscular collagen analysis. RESULTS: An increase in morphometric parameters (area, maximum and minimum diameters, Feret diameter, and minimum Feret) was observed in NMJs from the S and R groups in comparison with the C group, and there was also a loss of common NMJ circularity. The number of myofibers with central nuclei was higher in S (17 ± 3.9, P = .0083) and R (18.86 ± 14.42, P = .0498) than in C (6.8 ± 2.6). DISCUSSION: Gestational exposure to statins induced postpartum NMJ morphology alterations in soleus muscle, which may be caused by the remodeling of clusters of nicotinic acetylcholine receptors. This may be associated with the development and progression of SAMS observed in clinical practice.

Histomorphometric evaluation of soleus and lateral gastrocnemius muscles of animals submitted to pharmacological manipulation with fluoxetine / Evaluación histomorfométrica de los músculos sóleo y gastrocnemio lateral de animales sometidos a manipulación farmacológica con fluoxetina

The pharmacological manipulation with selective inhibitor of serotonin reuptake (SSRIs) can modify the operation of the serotonergic system and may facilitate or inhibit the action of this system, inducing changes in the morphology of the skeletal muscle of rats. The objective of this study was to evaluate the action of the treatment with fluoxetine during the critical period of the animal´s life on development of the soleus and lateral gastrocnemius muscles, under the aspects of weight, the number of nuclei of myocyte cells and cross-sectional area of muscle fibers. Twenty four (30 and 90-day-old) male Wistar rats were used. They were treated with saline solution (NaCl 0.9%; 1 ml/100 g of body weight) or fluoxetine (10 mg; 1 ml/100g of body weight). The animals were divided in Saline Group (GS-30 and GS-90) and Fluoxetine Group (GF-30 and GF-90). The fluoxetine group showed a reduction on weight (g) of soleus (p=0.046) and lateral gastrocnemius (p=0.02) muscles in rats with 90 days. A lesser number of myonuclei was observed in fluoxetine group than saline group of 30 days (soleus, p<0.001; lateral gastrocnemius, p0.007) and 90 days (soleus, p=0.002; lateral gastrocnemius, p0.038). The cross section area of fluoxetine groups is also smaller than the saline groups with 30 days (soleus, p=0.03; lateral gastrocnemius, p=0.041) and 90 days (soleus, p=0.042; lateral gastrocnemius, p=0.012). The treatment of fluoxetine during the critical period of development of the nervous system of rats, causes early changes in the structure of muscle fibers that seem to be related to reducing the weight of the soleus and gastrocnemius muscles only in late stage of the animal's life. Thus, the dosage used ISRS, suggests an inhibitory effect of 5-HT in relation to variables on the development of the skeletal muscle tissue of rats.

La manipulación farmacológica con inhibidores selectivos de la recaptación de la serotonina (ISRS) pueden cambiar el funcionamento del sistema serotoninérgico y facilitar o inhibir la acción de este sistema, induciendo cambios en la morfología del músculo esquelético de ratones. El objetivo fue analizar los efectos de la manipulación farmacológica neonatal con fluoxetina en el desarrollo de la masa muscular, número de núcleos y área de la sección transversa de las fibras de los músculos sóleo y gastrocnemio lateral. Se utilizaron 24 ratones Wistar machos, de 30 y 90 días de edad, tratados con solución salina (NaCl 0,9%, 1m/100 g de peso corporal) y fluoxetina (1 mg; 1 ml/100 g de peso corporal). Los animales fueron divididos en grupos con solución salina (GS-30 y GS-90) y fluoxetina (GF-30 y GF-90). El grupo tratado con fluoxetina mostró una reducción de peso (g) de los músculos sóleo (p=0,0046) y gastrocnemio lateral (p=0,02) en 90 días. Además, se observó en este mismo grupo una reducción de núcleos en 30 días (M. sóleo, p<0,001; M. gastrocnemio lateral, p0,007) así como en el período de 90 días (M. sóleo, p=0,002; M. gastrocnemio lateral, p0,038). También se observó reducción del área de la sección transversal en los animales tratados con fluoxetina durante el período de 30 días (M. sóleo, p=0,03; M. gastrocnemio lateral, p= 0,041;) y 90 días (M. sóleo, p=0,042; M. gastrocnemio lateral, p=0,012). El tratamiento con fluoxetina durante el período crítico del desarrollo del sistema nervioso de ratones, induce cambios prematuros en la estructura de la fibra muscular, los que parecen estar relacionados con la reducción de peso de los músculos sóleo y gastrocnemio en una fase tardía de vida del animal. En consecuencia, la dosis utilizada de ISRS, sugiere un efecto inhibidor de la 5-HT, en relación a las variables estudiadas sobre el desarrollo del tejido muscular esquelético de ratones.