Sex‐differences in Statin Effects: Long‐term Atorvastatin Administration Reduced LDL‐Cholesterol Levels and Body Weights only in Male Mice, but Decreased Voluntary Cage Activity in Male and Female Mice
Authors: Sanchez Pablo A. M. , Ghaffarejad Sina , Thio Marianne P. , Cardenas Valdivia Shany R. , Fannon McKenzie J. , Tompkins Alexandra M. , Lu Sun S. , Ronquillo Antoinette H. , Spellman Matthew O. , Zemljic-Harpf Alice E. 
Published: April 2020

Introduction

Statins inhibit HMG‐CoA reductase and are used to lower low‐density lipoprotein‐cholesterol (LDL‐C) for cardiovascular disease (CVD) prevention. Besides the benefits of reducing CVD‐related morbidity and mortality, adverse events have been reported by the FDA. Statin‐induced skeletal myopathy is the most reported statin adverse event. While the precise mechanism is undefined, there is considerable evidence that a statin‐induced impairment of oxidative phosphorylation within mitochondria is involved. We and others have previously shown that Atorvastatin (Ator) administration induces mitochondria alterations.

Rational

Because observational studies report a high incidence of statin‐myopathy and females seem to be more susceptible to statin adverse events, we aimed to generate a mouse model mimicking statin‐induced muscular side effects.

Methods

8‐week‐old male (M) and female (F) C57BL6J mice received either Ator (5mg/kg/day) or vehicle (Veh, 10% EtOH in water,) by daily oral gavage (4 groups, M+Ator, F+Ator, M+Veh, and F+Veh, n= 9–11 each). Body weights (BW) were recorded in two‐week intervals. 3‐month(m) post statin administration a lipid panel, liver enzymes, and creatine kinase (CK) was analyzed (n=8 each). Voluntary home cage activity was assessed 4‐m post statin treatment.

Results

A) 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). Long‐term Ator administration; B) induced lower BW (g) in male mice, but not in females starting at 1m post Ator administration (6m post body weight, Mean ± SEM; M+Veh 32.9g ± 0.8, M+Ator 28.4g ± 0.7, M+Veh versus M+Ator * p<0.0005; F+Veh 23.2g ± 0.6, F+Ator 22.7g ± 0.4, F+Veh vs F+Ator, not significant (ns)), C) reduced LDL‐C serum levels in M+Ator, but not in F+Ator mice (LDL‐C direct, Mean ± SEM; M+Veh 8.25 ± 0.41, M+Ator 7.12 ± 0.29, M+Veh versus M+Ator * p<0.04; F+Veh 9.25 ± 0.45, F+Ator 8.38 ± 0.56, F+Veh vs F+Ator, ns), D) did not alter total‐C or HDL‐C levels, E) elevated alkaline phosphatase levels in M+Ator but not in F+Ator mice, 5) did not alter CK serum levels, F) induced the development of gray hair only in M+Ator, and G) reduced voluntary cage activity in M+Ator and F+Ator mice, when compared to M+Veh and F+Veh.

Conclusion

Long‐term Ator administration reduced LDL‐C serum levels and BW in male mice but not in female mice. Although CK‐serum levels, a marker for skeletal muscle damage, were not significantly changed, voluntary cage activity was reduced in male and female Ator treated mice when compared to Veh treated controls. We suggest for the first time that long‐term Ator administration can induce a mouse‐model of statin‐induced myopathy.

Support or Funding Information

Veterans Medical Research Foundation Pilot Project Award: Alice Zemljic‐Harpf (PI), University of California, San Diego, ANES Research Seed Award 2019: Alice Zemljic‐Harpf (PI)