Cardiac and skeletal muscle changes associated with rosuvastatin therapy in dystrophic mdx mice

Abstract

Statins are prescribed to prevent and treat atherosclerotic cardiovascular and metabolic diseases but have controversial effects on skeletal muscles. While statins are a reported cause of myopathy, some studies have suggested that statins could potentially ameliorate dystrophy due to their pleiotropic effects on inflammation, myonecrosis, and autophagy. In the present study, we evaluated the potential benefit of rosuvastatin treatment on heart, limb, and diaphragm muscles in dystrophin‐deficient mdx mice at an early stage (45 days of age) of disease. Mdx mice received rosuvastatin (10 mg/kg) by gavage for 30 days beginning at 15 days of age. Normal C57BL/10 mice received rosuvastatin by the same route over the same interval. In the mdx group, rosuvastatin significantly increased IgG‐positive fibers (myonecrosis) and the inflammatory areas in the biceps brachii and diaphragm muscles and decreased the anterior limb muscle force (grip strength). Molecular markers of inflammation (TNF‐α and NF‐kB) and fibrosis (fibronectin) were not altered by rosuvastatin in mdx mice skeletal and cardiac muscles. In normal mice, rosuvastatin increased CK, TNF‐α (heart), NF‐kB (diaphragm), and fibronectin (heart and diaphragm). Inflammatory areas were seen in all normal muscles of rosuvastatin‐treated mice. Rosuvastatin did not benefit dystrophy in the mdx mice and was associated with inflammation in normal cardiac and skeletal muscles.

Effects of high rosuvastatin doses on hepatocyte mitochondria of hypercholesterolemic mice

“…In this sense, we observed that Ro at low doses (1 mg) did not significantly affect respiratory function, even in a prolonged treatment (59 days) compared with doses of 5 and 2.5 mg that significantly affected respiratory function from day 5. A study on mice with dystrophin protein deficiency who received 10 mg/kg of rosuvastatin, showed significantly increased areas of myonecrosis and inflammation, while mice without altered dystrophin who received the same doses showed increased levels of NF-Κβ, TNF-α as well as increased creatine kinase activity 31 , which suggests that high doses of rosuvastatin could potentiate the expression of some genes that encode proteins of inflammation pathways. In this sense, some authors presented that Rosuvastatin increases the expression of IL-10, and inhibits the overexpression of NF-κB 32 , 33 .…”

Simvastatin does not alleviate muscle pathology in a mouse model of Duchenne muscular dystrophy

“…Similarly, Amor et al suggested simvastatin treatment as a potential therapeutic agent in DMD due to its role in the regulation of cholesterol metabolism [ 14 ]. However, other studies performed with simvastatin [ 15 ] and rosuvastatin [ 16 ] did not confirm such favorable properties in animal models of DMD.…”

Rosuvastatin: Morphological and Respiratory Effects of High Doses on Liver Mitochondria from Hypercholesterolemic Mice

“…The studies of statins toxicity in the skeletal muscle have been greatly privileged [23]. Although it has been reported that the use of statins at low doses helps to recover the histological architecture of the liver in patients with non-alcoholic fatty liver [24], it has also been observed that in patients with medium doses and complicated with sepsis, rosuvastatin seems to accelerate liver damage and it has already been reported that in mice with dystrophin protein de ciency, which received doses of 10 mg / kg of rosuvastatin, the areas of myonecrosis and in ammation increased signi cantly, while in mice without alteration in dystrophin and subjected to the same doses, the level of NF-Κβ, TNF-α and creatine kinase activity increased signi cantly [25] a reason to think that high doses rosuvastatin could potentiate the expression of some genes that encode proteins of in ammation pathways such as those already mentioned. It has also been reported that at medium doses rosuvastatin modulates the expression of some molecules such as NF-Κβ [26].…”