Abstract
Background Recent clinical data have suggested that the chronic use of high-lipophilic statins impairs the regenerative capacity of skeletal muscle. Because this activity of statins is poorly understood, we aimed to investigate the effect of simvastatin (SIM) on postinjury myofibre regeneration. Methods The porcine model was used in this study. The animals were divided into two groups: nontreated (control; n=24) and SIM-treated (40 mg/day; n=24). On the 15th day (day 0) of the experiment, a bupivacaine hydrochloride- (BPVC-) induced muscle injury was established, and the animals were sacrificed in the following days after muscle injury. The degree of regeneration was assessed based on histopathological and immunohistochemical examinations. The presence and degree of extravasation, necrosis, and inflammation in the inflammatory phase were assessed, whereas the repair phase was evaluated based on the numbers of muscle precursor cells (MPCs), myotube and young myofibres. Results In the inflammatory phase, SIM increased the distribution and prolonged the period of extravasation, prolonged the duration of necrosis, and prolonged and enhanced the infiltration of inflammatory cells. In the repair phase, SIM delayed and prolonged the activity of MPCs, delayed myotube formation, and delayed and decreased the formation of young myofibres. Our results indicated that SIM did not improve blood vessel stabilization at the site of the injury, did not exert an anti-inflammatory effect, prolonged and enhanced the inflammatory response, and impaired MPC activity, differentiation, and fusion. Moreover, SIM appeared to reduce M1 macrophage activity, resulting in slower removal of necrotic debris and sustained necrosis. Conclusion This study shows that SIM negatively affects the inflammatory and repair phases of the postinjury muscle regeneration. These findings are unique, strengthen the available knowledge on the side effects of SIM, and provide evidence showing that statin therapy is associated with an increased risk of impairment of the regenerative capacity of muscle.
Highlights
Postinjury skeletal muscle regeneration is a complex process, and its success depends on the precise control of a sequence of events
In the control animals, the mean extension of necrosis did not differ significantly between days 7, 10, and 14, and, at these time points, necrosis was restricted to single fibres or was not detected (Figure 3(b)), which indicated that the final level of necrosis was reached on day 7 in this group. These results demonstrated that SIM prolonged the duration of necrosis in bupivacaine hydrochloride- (BPVC-)injured muscles by one time point compared with the control animals, irrespective of the severity of this process in the statin-treated animals
On day 5, statistically significant differences in this parameter were not found between the groups; on days 7 and 14, but not day 10, the mean myotube number was considerably increased (day 7: P < 0.01; day 14: P < 0.01; Figure 4(b)) in the SIM-treated animals compared with the control values. These results indicated that SIM delayed myotube formation and prolonged their presence in the repair phase of BPVCinjured muscle regeneration
Summary
Postinjury skeletal muscle regeneration is a complex process, and its success depends on the precise control of a sequence of events. The initial inflammatory phase, which is characterized by myofibre necrosis, extravasation, and neutrophil infiltration and is rapidly followed by macrophage recruitment and phagocytosis of the myofibre debris, is very important for muscle reconstruction During this phase, inflammatory cells interact with each other, and neutrophils are the first cell population found in acutely injured muscle, which peaked at 12-24 h postinjury. This study shows that SIM negatively affects the inflammatory and repair phases of the postinjury muscle regeneration These findings are unique, strengthen the available knowledge on the side effects of SIM, and provide evidence showing that statin therapy is associated with an increased risk of impairment of the regenerative capacity of muscle
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