Male and female mice display sex differences in lipid metabolism: Long-term atorvastatin or rosuvastatin administration impaired locomotive activity and cardiac relaxation in both sexes
Authors: Alam Sifat , Gierden Kyle , Ghaffarejad Sina , Dixit Mihir , Sanchez Pablo , Thio Marianne , Lu Sun , Ronquillo Antoinette , Zemljic-Harpf Alice 
Published: May 2023

Introduction: Statins are HMG-CoA reductase inhibitors and are among the most used drugs. Statins are prescribed to reduce low density lipoprotein-Cholesterol (LDL-C) levels for the prevention and treatment of cardiovascular disease. HMG-CoA reductase is ubiquitously expressed in the ER-membrane. The most common adverse effect are statin-associated muscle symptoms (SAMS) ranging from muscle weakness, pain, cramps, exercise intolerance to rare cases of rhabdomyolysis. Women are more likely to report SAMS, but the mechanisms of sex differences in statin adverse events are unknown. Effects on mitochondrial pathways play an important role in statin-induced myopathy. We previously showed that the lipophilic atorvastatin (Ator), but not the hydrophilic pravastatin, increased sudden death in cardiomyopathic mice due to mitochondrial alteration. Because hydrophilic statins are thought to be better tolerated due to less intracellular access, we hypothesized that the hydrophilic rosuvastatin (Rosu) may lead to fewer statin adverse effects when compared to Ator. Methods: 8-week-old male (M) and female (F) C57BL6J mice received either Ator (5mg/kg), Rosu (5mg/kg), or vehicle (Veh, 10% EtOH in water,) by daily oral gavage (6 groups, M+Ator, F+Ator, M+Rosu, F+Rosu, M+Veh, and F+Veh, n= 9-12 each). A lipid panel, liver enzymes, and creatine kinase (CK) were analyzed 4-month(m) post statin administration (n=8 each). Voluntary home cage activity was assessed 4-months (m) and echocardiography performed at 10-m after treatment start. Results: Prior to treatment M+Veh mice presented higher total-C and high-density lipoprotein (HDL)-C serum levels than F+ Veh mice (total- C mg/dl, Mean ± SEM; M+Veh 131.4 ± 7.4, F+Veh 90.5 ± 4.8, M+Veh vs F+Veh, * p<0.0004, and HDL-C mg/dl, Mean ± SEM; M+Veh 82.8 ± 3.3, F+Veh 58.6 ± 3.4, M+Veh vs F+Veh, * p<0.0002). Ator and Rosu administration did not alter CK levels but reduced voluntary total distance moved in M+Ator, M+Rosu, F+Ator, and F+Rosu mice, when compared to M+Veh and F+Veh. After 10m-long daily statin or vehicle administration, echocardiography revealed that M+Ator, M+Rosu, F+Ator, and F+Rosu presented preserved systolic ejection fraction (%EF) while tissue Doppler analysis detected decreased E’/A’ ratios (M+Veh 2.38±0.15, M+Ator 1.47±0.21, M+Rosu 1.5±0.18, F+Veh 1.99±0.15, F+Ator 1.11± 0.17, F+Rosu 0.97± 0.14, statin vs statin per sex non-significant, statin vs Veh per sex p < 0.004, n=9-12 each). Conclusion: Long-term Ator and Rosu administration reduced voluntary cage activity and induced diastolic dysfunction with preserved systolic function in male and female mice to a similar degree. Despite its hydrophilicity, the greater LDL-C lowering efficacy and longer half-live of Rosu may attribute to these findings. In male and female mice, we show for first time that long-term Ator and Rosu administration induced physiological alterations found in heart failure with preserved ejection fraction. Veterans Medical Research Foundation/San Diego Pilot Project Award, Zemljic-Harpf (PI), UC San Diego ANES Research Seed Award, Zemljic-Harpf (PI) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.