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Statin Treatment Attenuates Muscular and Cardiorespiratory Adaptations to Treadmill Training in Mice

Individuals with hypercholesterolemia are at increased risk for developing heart disease and are often prescribed statins, the most effective cholesterol‐lowering drugs, as well as exercise. A highly reported side effect of statins is muscle pain and dysfunction that may be exacerbated with exercise. However, we previously reported that muscle force and cardiorespiratory fitness were not negatively impacted by statin treatment during treadmill training in mice with genetically high cholesterol, ApoE−/−. Both exercise and statins have been associated with reduced inflammatory cytokines such as interleukin‐6 (IL‐6). To date, no studies have investigated if statin treatment in C57 mice (wild type control for ApoE−/−) impacts muscular and cardiorespiratory adaptations to treadmill training. We hypothesized that statin treatment would negatively impact muscular and cardiorespiratory adaptations to treadmill training, and such impairments would be associated with higher inflammatory cytokine levels. Adult mice were divided into 4 groups (n= 8–10/group) and completed 14d of treadmill training (60 min/day) or remained sedentary while receiving daily placebo or atorvastatin. Cardiorespiratory adaptations were assessed by pre‐ and post‐maximal treadmill tests. Plantarflexor muscle force and fatigue (% of max force after 10 contractions) were measured in vivo. Muscle IL‐6 and vascular endothelial factor (VEGF) protein levels were quantified with ELISA. Data were analyzed with 2‐way ANOVAs and post‐hoc tests. Atorvastatin was associated with decreased maximal isometric force relative to body mass in treadmill groups only with no difference in sedentary groups (1.6±0.06 vs. 1.1±0.05 and 1.6±0.07 vs. 1.5±0.08 g/g body mass, respectively, p<0.05). Muscle fatigability was similar among all conditions. Cardiorespiratory fitness increased in both treadmill groups; however, increases were greater in placebo than statin mice with 13:30±2:00 and 7:55±0:42 min increases in test time, respectively (p<0.05). Maximal test time was unchanged in sedentary groups. Muscle IL‐6 levels were unchanged with treadmill training; however, statin treatment was associated with decreased muscle IL‐6 compared to placebo in both sedentary and treadmill groups (p<0.05). Statin treatment decreased IL‐6 66 and 82% compared to placebo, in sedentary and treadmill groups, respectively (p<0.05). Treadmill training was associated with increases in muscle VEGF in placebo group only (p<0.05). These findings suggest statin treatment impairs muscle strength when combined with treadmill training and attenuates increases in maximal test time with training. It is unclear whether the treadmill test performance was due to muscular and/or cardiorespiratory limitations; however, reductions in muscle strength suggest a muscular component. The finding that statin treatment prevented training associated increases in muscle VEGF suggest a potential vascular component. These findings are in contrast to results in ApoE−/− mice in which statin treatment did not impair muscular or cardiorespiratory adaptations to treadmill training. Further research is needed to determine genetic and/or cellular mechanisms whereby statin treatment impacts skeletal muscle.