PGC‐1α plays a pivotal role in simvastatin‐induced exercise impairment in mice

Abstract

Aim Statins decrease cardiovascular complications, but can induce myopathy. Here, we explored the implication of PGC‐1α in statin‐associated myotoxicity. Methods We treated PGC‐1α knockout (KO), PGC‐1α overexpression (OE) and wild‐type (WT) mice orally with 5 mg simvastatin kg−1 day−1 for 3 weeks and assessed muscle function and metabolism. Results In WT and KO mice, but not in OE mice, simvastatin decreased grip strength, maximal running distance and vertical power assessed by ergometry. Post‐exercise plasma lactate concentrations were higher in WT and KO compared to OE mice. In glycolytic gastrocnemius, simvastatin decreased mitochondrial respiration, increased mitochondrial ROS production and free radical leak in WT and KO, but not in OE mice. Simvastatin increased mRNA expression of Sod1 and Sod2 in glycolytic and oxidative gastrocnemius of WT, but decreased it in KO mice. OE mice had a higher mitochondrial DNA content in both gastrocnemius than WT or KO mice and simvastatin exhibited a trend to decrease the citrate synthase activity in white and red gastrocnemius in all treatment groups. Simvastatin showed a trend to decrease the mitochondrial volume fraction in both muscle types of all treatment groups. Mitochondria were smaller in WT and KO compared to OE mice and simvastatin further reduced the mitochondrial size in WT and KO mice, but not in OE mice. Conclusions Simvastatin impairs skeletal muscle function, muscle oxidative metabolism and mitochondrial morphology preferentially in WT and KO mice, whereas OE mice appear to be protected, suggesting a role of PGC‐1α in preventing simvastatin‐associated myotoxicity.

Simvastatin Impairs Glucose Homeostasis in Mice Depending on PGC-1α Skeletal Muscle Expression

“…The simvastatin dose was calculated as described by Reagen-Shaw et al [28] and corresponds to approximately 0.4 mg/kg per day in humans, which is a normally-used dose. Moreover, this dose was selected based on our previous studies where mice showed peak plasma concentrations similar to human patients treated with 40 mg of simvastatin per day [14,21,29].…”

“…Several studies from our group have shown that mitochondrial dysfunction is an important component of statin-associated skeletal muscle damage [7,[11][12][13]. These mitochondrial defects increase mitochondrial reactive oxygen species (ROS) production, which partly accounts for apoptosis of muscle fibers and promotes fiber degeneration and remodeling [11,13,14].…”

Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples

“…In mice treated daily for three weeks at 5 mg/kg, grip strength and muscle endurance capacity were decreased while plasma lactate levels were elevated after exercise compared to control mice. Additionally, disturbances of mitochondrial function could be detected with impaired oxidative metabolism [ 39 , 40 ].…”

“…The clinical manifestations start from myalgia, myopathy to potentially fatal rhabdomyolysis in rare cases [ 37 , 38 ]. These adverse skeletal muscle effects were observed at the doses used in this study [ 39 , 40 , 41 ]. Therefore, we assessed whether inhibition of de novo cholesterol formation [ 38 , 42 ] and the production of intermediates of cholesterol synthesis such as ubiquinone (CoQ10) and dolichols [ 38 ] by simvastatin might disrupt bile acid homeostasis and contribute to myotoxicity.…”

Exercise and cardiovascular diseases

“…In particular, lifelong exercise showed an increase in mitochondrial turnover indicated by strong mitophagy matched with increased mitochondrial fusion and decreased fission 23 . PGC‐1α, master regulator of mitochondrial biogenesis and apparent key player in the hepatic stress response to bouts of acute exercise, 24 may assume a critical role in preventing simvastatin‐associated myotoxicity 25 …”