The Impact of Exercise on Statin-Associated Skeletal Muscle Myopathy.

HMG-CoA reductase inhibitors (statins) are the most effective pharmacological means of reducing cardiovascular disease risk. The most common side effect of statin use is skeletal muscle myopathy, which may be exacerbated by exercise. Hypercholesterolemia and training status are factors that are rarely considered in the progression of myopathy. The purpose of this study was to determine the extent to which acute and chronic exercise can influence statin-induced myopathy in hypercholesterolemic (ApoE-/-) mice. Mice either received daily injections of saline or simvastatin (20 mg/kg) while: 1) remaining sedentary (Sed), 2) engaging in daily exercise for two weeks (novel, Nov), or 3) engaging in daily exercise for two weeks after a brief period of training (accustomed, Acct) (2x3 design, n = 60). Cholesterol, activity, strength, and indices of myofiber damage and atrophy were assessed. Running wheel activity declined in both exercise groups receiving statins (statin x time interaction, p<0.05). Cholesterol, grip strength, and maximal isometric force were significantly lower in all groups following statin treatment (statin main effect, p<0.05). Mitochondrial content and myofiber size were increased and 4-HNE was decreased by exercise (statin x exercise interaction, p<0.05), and these beneficial effects were abrogated by statin treatment. Exercise (Acct and Nov) increased atrogin-1 mRNA in combination with statin treatment, yet enhanced fiber damage or atrophy was not observed. The results from this study suggest that exercise (Nov, Acct) does not exacerbate statin-induced myopathy in ApoE-/- mice, yet statin treatment reduces activity in a manner that prevents muscle from mounting a beneficial adaptive response to training.

Resveratrol supplementation reduces aortic atherosclerosis and calcification and attenuates loss of aerobic capacity in a mouse model of uremia.

The polyphenolic compound resveratrol (RSV) has been studied for its protective effects on a variety of conditions, including cardiovascular disease (CVD), reduced exercise capacity, and bone disease. Individuals with chronic kidney disease suffer from a variety of these comorbid conditions, but the efficacy of RSV supplementation in this population is unknown. The objective of this study was to determine the efficacy of resveratrol feeding on factors related to CVD, aerobic capacity, and bone health in a mouse model of uremia. At 8 weeks of age, 28 female apolipoprotein E⁻/⁻ mice underwent a two-step surgical procedure to induce uremia and were randomized to one of the two treatment groups for 16 weeks: 0.04% w/w resveratrol supplemented diet (group designated as RSV) (n=12) or control diet (group designated as CON) (n=16). Cardiovascular risk was determined by analysis of aortic atherosclerotic lesion area and aortic calcium, aerobic capacity was measured by maximal oxygen consumption/maximal aerobic capacity (VO(2max)) testing, and bone microarchitecture was assessed by microcomputed tomography. RSV animals had significantly fewer aortic atherosclerotic lesions at the site of the ascending aorta and lower aortic calcium at the branch of the coronary arteries compared with CON. Furthermore, there was a significant decline in VO(2max) from baseline to final testing in the CON group, but VO(2max) was preserved in the RSV group. Last, RSV had no significant effect on bone architecture. These data indicate that RSV supplementation improves vascular health and preserves aerobic capacity in a model of uremia, suggesting RSV supplementation could be examined as a therapeutic strategy for a critically ill population.

Soy protein diet and exercise training increase relative bone volume and enhance bone microarchitecture in a mouse model of uremia.

Soy protein consumption and exercise training have been widely studied for their effects on the vasculature and bone in healthy populations, but little is known about the effectiveness of these interventions in chronic kidney disease (CKD). Cardiovascular disease and bone fracture risk are significantly elevated in CKD, and current pharmacological interventions have been unsuccessful in treating these conditions simultaneously. The purpose of this study was to compare the effects of a soy protein diet and endurance exercise training, alone or in combination, on cardiovascular and bone health in a mouse model of renal insufficiency. At 8 weeks of age, 60 female apolipoprotein E(-/-) mice underwent a two-step surgical procedure to induce uremia. These mice were then randomized at 12 weeks of age to one of four treatment groups for the 16-week intervention period: sedentary, control diet (n = 16); sedentary, soy protein diet (n = 18); exercise, control diet (n = 14); and exercise, soy protein diet (n = 12). There were no significant treatment effects on atherosclerotic lesion areas or aortic calcium deposits. We demonstrated a significant main effect of both diet and exercise on relative bone volume, trabecular number, trabecular separation, and trabecular connective density in the proximal femur as measured by microcomputed tomography. There were no treatment effects on trabecular thickness. We also showed a main effect of diet on plasma urea levels. These data suggest that soy protein intake and exercise training exert beneficial effects on properties of bone and plasma urea levels in mice with surgically induced renal impairment.

Endurance exercise training reduces gallstone development in mice.

Gallstones form when the ratio of bile cholesterol to bile acids and phospholipids is elevated, causing cholesterol to precipitate. Physical inactivity is hypothesized to increase gallstone development, but experimental evidence supporting this is lacking, and potential mechanisms for the antilithogenic effects of exercise have not been described. The purpose of this study was to examine the effect of endurance exercise training on gallstone formation and the expression of genes involved in bile cholesterol metabolism in gallstone-sensitive (C57L/J) mice. At 10 wk, 50 male mice began a lithogenic diet and were randomly assigned to an exercise-training (EX) or sedentary (SED) group (n = 25 per group). Mice in the EX group ran on a treadmill at approximately 15 m/min for 45 min/day for 12 wk. At the time animals were euthanized, gallstones were collected, pooled by group, and weighed. The weight of the gallstones was 2.5-fold greater in the SED mice compared with EX mice (143 vs. 57 mg, respectively). In the EX mice, hepatic expression of the low-density lipoprotein receptor (LDLr), scavenger receptor class B type 1 (SRB1), and sterol 27 hydroxylase (Cyp27) was increased by approximately 2-fold (P < 0.05 for each). The LDLr and SRB1 increase cholesterol clearance by low-density lipoprotein and high-density lipoprotein particles, respectively, while Cyp27 promotes the catabolism of cholesterol to bile acids. Taken together, these data indicate that exercise promotes changes in hepatic gene expression that increase cholesterol uptake by the liver but simultaneously increase the catabolism of cholesterol to bile acids, effectively reducing cholesterol saturation in the bile. This suggests a mechanism by which exercise improves cholesterol clearance from the circulation while simultaneously inhibiting gallstone formation.