Cholesterol and Statin in Healthy Adults

Overview

Statins are a class of drugs that are the most commonly prescribed medications in developing countries. Statins act on the enzyme HMG-CoA reductase to inhibit its conversion to mevalonate, a precursor for cholesterol synthesis. Subsequently statins are prescribed to patients with relatively high blood cholesterol levels. However, taking statins does not come without side effects. Most notably, the effects of statins on muscle wasting have been studied extensively. This includes up-regulation of the ubiquitin proteasome system, muscle cell damage and rhabdomyolysis, elevated creatine kinase, and mitochondrial dysfunction. Due to the negative side effects of statin therapy, additional therapies are warranted to help offset the effects on muscle wasting. Loss of muscle mass is a significant concern as it is associated with a reduction in muscle strength and power (Ferrando et al., 1996; Creditor, 1993). This condition is observed in aging, disease states, and long periods of unloading such as hospital admission and can lead to disability, increased falls, loss of independence, and mortality. Subsequently, there is a critical need to develop interventions to counteract this loss of muscle mass and strength. Exercise is one such intervention, however, in some cases may not be a feasible option. For instance, exercise has been demonstrated to exacerbate the muscle side of effects of statins. Subjects complain of increased muscle soreness and have elevated creatine kinase levels and they also do not want to take statins anymore (Kearns et al., 2008; Parker et al., 2012; Sinzinger et al., 2004). Because of this limitation, there is a critical need to develop other interventions that can prevent the loss of muscle mass during statin use.

The use of nutritional interventions have gained much attention and are being explored for their ability to increase muscle mass and/or attenuate loss of muscle mass. Leucine, isoleucine, and valine are branched chain amino acids that have been studied extensively and have been shown to stimulate muscle anabolism. Beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of leucine, has been suggested to play a significant role in preserving muscle mass in situations that favor muscle mass loss. This is thought to occur through stabilizing sarcolemma integrity, reduced proteasome activity and expression of the proteasome 20S subunit, inhibition of apoptosis, and by activation of skeletal muscle satellite cells. Furthermore, in a catabolic-induced myotube and a murine adenocarcinoma cell line, HMB (50µM) was more potent in reversing the increased protein degradation and decreased protein synthesis compared to a higher dose of leucine (1mM). Similar findings were reported in a rodent cancer model. These data suggests that HMB plays a significant role in preventing muscle wasting. Understanding the metabolic fate of HMB is crucial to developing strategies to increase HMB concentrations in populations that are subjected to muscle wasting. The objective of this application is to determine if a cholesterol lowering statin alters HMB metabolism in healthy adults. The Researchers will test the hypotheses that with statin administration, HMB metabolism and urinary excretion is affected and that this will have an unknown effect on the production of HMB and the response to intake of HMB precursors like leucine.