THE EFFECTS OF HYPERCHOLESTEROLEMIA ON SKELETAL MUSCLE REGENERATION: A LOOK INTO PROTEIN SYNTHESIS AND CELL CYCLE REGULATION

Joshua Ragland, Lemuel Brown, Alyssa Papineau, & Tyrone Washington; Exercise Muscle Biology Laboratory and Human Performance Lab, University of Arkansas, Fayetteville, AR Hypercholesterolemia is a pathology in which total serum cholesterol is above 240mg/dL. Having high cholesterol puts one at risk for developing cardiovascular disease (CVD), the number one cause of death in America. ApoE helps regulate serum cholesterol levels by adding in transport of cholesterol into the cells, as well as, to the liver. Mice genetically altered to produce no apoE (apoE-KO) present a model that demonstrates the effects of hypercholesterolemia. Damage to skeletal muscle, whether caused by injury, resistance exercise, or disease stimulates a complex regenerative response. The effects of high cholesterol on the skeletal muscle regenerative response are not known. PURPOSE: To determine if skeletal muscle regeneration is altered in apoE-KO mice by measuring protein synthesis regulator IGF-1 and cell cycle regulator cyclin D1. METHODS: Female C57/BL6 (WT) and apoE KO were assigned to either an uninjured or injured group. To induce skeletal muscle damage, the tibialis anterior (TA) was injected with bupivacaine. In the uninjured group, the TA was injected with phosphate buffered saline. TA muscle was extracted 3 days post-injection. Quantitative PCR was conducted to determine gene expression for IGF-1 and cyclin D1. RESULTS: TA mass to tibia length decreased 20.8% (2.4 ± 0.1 vs. 1.9 ±0.2 mg/mm) (p \u3c 0.05) 3 days post injection in WT mice. In apoE-KO mice, TA mass to tibia length decreased 15.4% (2.98 ± 0.19 vs. 2.52 ± 0.12 mg/mm) (p \u3c 0.05) 3 days post injection. IGF-1 gene expression increased 5-fold (p \u3c 0.05) and 3.5-fold (p \u3c 0.05) during skeletal muscle regeneration in WT and aopE-KO mice, respectively. Cyclin D1 increases 1.75-fold (p \u3c 0.05) in WT mice 3 days post-bupivacaine injection. However, cyclin D1 gene expression increased 12-fold (p \u3c 0.05) 3 days post-bupivacaine injection in apoE-KO mice. CONCLUSION: This data shows that hypercholesterolemia associated with apoE-KO mice induced a greater increase in cyclin D1 gene expression than observed in the WT mouse. A deficiency in the apoE gene has no effect on IGF-1 expression but does however have a differential effect on cyclin D1 expression. The apoE-KO mice were a kind gift from Rigel Pharmaceuticals