A short-term statin treatment changes the contractile properties of fast-twitch skeletal muscles.

Antoine Boulanger Piette,Sébastien S Dufresne,Jérôme Frenette

doi:10.1186/s12891-016-1306-2

Abstract

BackgroundCumulative evidence indicates that statins induce myotoxicity. However, the lack of understanding of how statins affect skeletal muscles at the structural, functional, and physiological levels hampers proper healthcare management. The purpose of the present study was to investigate the early after-effects of lovastatin on the slow-twitch soleus (Sol) and fast-twitch extensor digitorum longus (EDL) muscles.MethodsAdult C57BL/6 mice were orally administrated with placebo or lovastatin [50 mg/kg/d] for 28 days. At the end of the treatment, the isometric ex vivo contractile properties of the Sol and EDL muscles were measured. Subtetanic and tetanic contractions were assessed and contraction kinetics were recorded. The muscles were then frozen for immunohistochemical analyses. Data were analyzed by two-way ANOVA followed by an a posteriori Tukey’s test.ResultsThe short-term lovastatin treatment did not induce muscle mass loss, muscle fiber atrophy, or creatine kinase (CK) release. It had no functional impact on slow-twitch Sol muscles. However, subtetanic stimulations at 10 Hz provoked greater force production in fast-twitch EDL muscles. The treatment also decreased the maximal rate of force development (dP/dT) of twitch contractions and prolonged the half relaxation time (1/2RT) of tetanic contractions of EDL muscles.ConclusionsAn early short-term statin treatment induced subtle but significant changes in some parameters of the contractile profile of EDL muscles, providing new insights into the selective initiation of statin-induced myopathy in fast-twitch muscles.

Highlights

Cumulative evidence indicates that statins induce myotoxicity
Since statins are widely prescribed and since statin-induced myopathy (SIM) may lead to the discontinuation of treatment, sometimes after less than 2 weeks, we investigated the functional impact of a short-term lovastatin treatment (28 days) on the ex vivo contractile properties of slow-twitch Sol and fast-twitch extensor digitorum longus (EDL) muscles We investigated the impact of a shortterm lovastatin treatment on muscle integrity, serum creatine kinase release, and myosin phenotype in fast-twitch EDL muscles
We showed that a short-term lovastatin treatment induces subtle but significant changes in the contractile profile of fast-twitch EDL muscles

Summary

Introduction

Cumulative evidence indicates that statins induce myotoxicity. the lack of understanding of how statins affect skeletal muscles at the structural, functional, and physiological levels hampers proper healthcare management. While the pathophysiology of SIM is heterogeneous and poorly understood, it appears to be multifactorial and may involve multiple pathophysiological defects, including genetic predisposition [4], early [9], the inhibition of protein geranylgeranylation [10], ubiquinone depletion [11, 12], monocarboxylate transporter 4 expression [13, 14], loss of t-tubular region architecture [15, 16], altered membrane fluidity [17], and immune-mediated necrotis [18]. Ca2+ is rapidly transported back into the SR lumen by SERCA [sarco (endo) plasmic reticulum Ca2+ATPase], an ATP-dependent Ca2+ pump, inducing muscle relaxation and preparing the muscle for the contraction. Myoplasmic Ca2+ regulates protein synthesis, protein degradation, and fiber phenotype by controlling Ca2+-sensitive proteases, transcription factors, and mitochondrial adaptations

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