SIM has major social and economic consequences. The lack of understanding of how statins impair muscle function at the molecular, cellular, and physiological levels creates numerous barriers to effective treatment [
2]. SIM can result in the discontinuation of treatment, leaving specific patients at risk of potential adverse cardiovascular events [
43]. The onset of SIM is most likely multifactorial, resulting in multiple physiological impairments in patients with ill-defined musculoskeletal conditions. We showed that a short-term lovastatin treatment induces subtle but significant changes in the contractile profile of fast-twitch EDL muscles.
We also showed that a short-term 28-day lovastatin treatment did not affect the morphology, integrity, or maximal force output of slow-twitch Sol and fast-twitch EDL muscles. However, the force production of subtetanic contractions at 10 Hz was significantly higher while the ½ RT at P
0 of EDL muscles was prolonged in statin-treated mice compared to control mice. From a physiological standpoint, a prolonged ½ RT at P
0 should favor a longer lasting Ca
2+ transient, leading to a gain of force production at a low frequency stimulation (10 Hz). Furthermore, the prolonged ½ RT in fast-twitch EDL muscles also suggested that Ca
2+ reuptake by the SR is impaired. Ca
2+ reuptake is almost exclusively mediated by SERCA-1a in fast-twitch fibers. SERCA is critical for Ca
2+ homeostasis and reuptake by the SR following contractions, allowing cytosolic Ca
2+ concentrations to return to baseline levels and enabling muscle relaxation [
19,
44]. Consistent with our results and a role for statins in the regulation of Ca
2+ handling, chronic 2-month-long treatments of rats with fluvastatin [20 mg/kg] increase the resting cytosolic Ca
2+ concentration of EDL muscle fibers by 60 % but have no impact on muscle integrity and grip strength [
21]. Pierno et al. (1999) also reported that EDL muscles from simvastatin-treated rats require less depolarization to contract, suggesting that they contain higher levels of cytosolic Ca
2+ [
45]. Liantonio et al. (2007) proposed that mitochondria are responsible for the earlier event, with a subsequent and larger Ca
2+ leakage from SR stores, and that extracellular Ca
2+ channels play a negligible role in the increase in cytosolic Ca
2+. Applying simvastatin to human skeletal muscle fibers triggers a wave of cytosolic Ca
2+ originating from the SR Ca
2+ store, while ryanodine and SERCA inhibitors almost completely abolish the increase in cytosolic Ca
2+ [
46]. These findings indicated that the loss of Ca
2+ homeostasis associated with SIM may be caused by the release of Ca
2+ from mitochondria and/or the SR store [
21,
22,
46]. The prolonged ½ RT and gain of force at a low stimulation frequency provide additional support for the notion that Ca
2+ handling is impaired, especially in fast-twitch muscles, following statin treatments.
We also showed that the maximum dP/dT, i.e. the peak rate of force development, is 22.4 % lower in EDL muscles from statin-treated mice. A decrease in dP/dT should be associated with a change in muscle phenotype from fast-to slow-twitch. In rats, a simvastatin-treatment induces a 15 % shift from the fast MyHC IIb/x to the slower MyHC IIa phenotype, which is associated with a loss of power output (−41 %) and a reduced shortening velocity (−23 %), with no change in isometric force or CK levels [
47]. However, we did not detect any phenotypic changes in EDL muscles after the 28-day lovastatin treatment. Since cholesterol plays a pivotal role in the composition, fluidity, and integrity of the cell membrane, it is possible that statin treatments alter the compliance/rigidity of the muscle membrane, thus decreasing dP/dT. In other words, the contractile component shortens and stretches the elastic component (membrane, extracellular matrix, tendon) by the same amount during contractions. A more compliant membrane/extracellular matrix in statin-treated mice would lower dP/dT. Accordingly, statins cause a deterioration of the biomechanical properties of the Achilles tendon [
48] and may be a risk factor for muscle and tendon ruptures and tendinopathies [
49,
50]. Statins have thus pleiotropic properties, but the exact mechanism by which they decrease dP/dT requires further investigation.