Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle

Abstract

Statins and fibrates can cause myopathy. To further understand the causes of the damage we performed a proteome analysis in fast-twitch skeletal muscle of rats chronically treated with different hypolipidemic drugs. The proteomic maps were obtained from extensor digitorum longus (EDL) muscles of rats treated for 2-months with 10mg/kg atorvastatin, 20mg/kg fluvastatin, 60mg/kg fenofibrate and control rats. The proteins differentially expressed were identified by mass spectrometry and further analysed by immunoblot analysis. We found a significant modification in 40 out of 417 total spots analysed in atorvastatin treated rats, 15 out of 436 total spots in fluvastatin treated rats and 21 out of 439 total spots in fenofibrate treated rats in comparison to controls. All treatments induced a general tendency to a down-regulation of protein expression; in particular, atorvastatin affected the protein pattern more extensively with respect to the other treatments.Energy production systems, both oxidative and glycolytic enzymes and creatine kinase, were downregulated following atorvastatin administration, whereas fenofibrate determined mostly alterations in glycolytic enzymes and creatine kinase, oxidative enzymes being relatively spared. Additionally, all treatments resulted in some modifications of proteins involved in cellular defenses against oxidative stress, such as heat shock proteins, and of myofibrillar proteins. These results were confirmed by immunoblot analysis. In conclusions, the proteomic analysis showed that either statin or fibrate administration can modify the expression of proteins essential for skeletal muscle function suggesting potential mechanisms for statin myopathy.

Naturally Produced Lovastatin Modifies the Histology and Proteome Profile of Goat Skeletal Muscle

“…Lovastatin supplementation had impaired the energy production system in the skeletal muscle, particularly in the metabolism of carbohydrate and creatine. Similar observations have been reported on the extensor digitorum longus muscle of rats treated for 2-months of 10mg atorvastatin/kg BW and 20mg fluvastatin/kg BW [29]. The impairment in the energy production system could play a major role in the development of muscle damage, which is consistent with the adverse effects observed on the longissimus thoracis et lumborum muscle through histological examination.…”

“…Through this metabolic process, high energy adenosine triphosphate (ATP) molecules and reduced nicotinamide adenine dinucleotide (NADH) are generated. Similar observations of down-regulation of glycolytic enzymes in the skeletal muscle have also reported previously in rat and the down-regulation of glycolytic enzymes is a symptom of energy production failure, and can contribute to muscle damage [29]. In humans, hereditary muscle glycogenoses are characterized by defective glycolytic enzymes and leads to different degree of myopathy [30].…”

Spruce Needle Polyprenols Protect Against Atorvastatin-Induced Muscle Weakness and do not Influence Central Nervous System Functions in Rats

“…There are several case reports of induction of inflammatory myopathies (i.e., polymyositis and dermatomyositis) by statins, but many (25 cases of a histologically distinct statin myopathy) muscle biopsies demonstrated necrotising myopathy without significant inflammation. Other studies showed that atorvastatin (10 mg/kg for 2 months in rats) may induce a down-regulation of the expression of proteins essential for skeletal muscle function (Camerino et al, 2011).…”

Statin therapy and plasma coenzyme Q10 concentrations—A systematic review and meta-analysis of placebo-controlled trials

“…The mechanisms activated in statin-induced myopathy include the inhibition of mevalonic acid production, a precursor in the synthesis of ubiquinone (CoQ10) [12], the modification of the expression of proteins needed in cellular protection against oxidative stress [13], the changes in the mitochondrial respiratory chain with consecutive depolarization of the mitochondrial internal membrane, alteration of calcium homeostasis and appearance of "calcium waves" [14]. Since mitochondrial dysfunction might be induced by CoQ10 deficiency, a meta-analysis of randomized controlled trials analyzed the effects of CoQ10 supplementation in patients with statin-induced myopathy.…”