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Kronos Institute Statin Pilot Study

Statins, Muscle, Mitochondrial function, and Aging (Kronos Institute Statin Study)

Principal Investigator: Tinna Traustadóttir, PhD
Co-investigator: S. Mitchell Harman, MD, PhD

Hydroxy-Methylglutaryl-Coenzyme A (HMG CoA) reductase inhibitors (statins) are the most effective available pharmaceutical agents to lower cholesterol and reduce risk for coronary artery disease. However, use of statins is frequently associated with complaints of skeletal muscle problems such as aching, cramping, and weakness, (and rarely, rhabdomyolysis, a life-threatening breakdown of muscle tissue). Blocking HMG-CoA reductase is known to reduce endogenous synthesis of coenzyme Q₁₀ (CoQ₁₀), a co-factor for oxidative phosphorylation, the energy generating process that drives skeletal muscle function. CoQ₁₀ depletion could compromise function of the mitochondria (subcellular factories for the high energy compound, ATP) resulting in altered substrate kinetics and skeletal muscle metabolism.

The reduction in CoQ₁₀ levels following statin therapy is expected to be modest and may not result in detectible changes in muscle function at rest. However, during exercise or other physical activity, as the heart and skeletal muscles are required to perform increasing amounts of work, it is likely that compromised function due to CoQ₁₀ depletion might become evident. Furthermore, older individuals may be more susceptible to statin-associated muscle problems because CoQ₁₀ levels have been shown to decrease with age, and aging is associated with decreased skeletal muscle reserve which may be related in part to cumulative mitochondrial damage and dysfunction.

This study tested the hypothesis that high-dose statin treatment would result in decreased work capacity in older men and women, secondary to a reduction in CoQ₁₀ levels.

Status:	Completed
Participants:	Ten men and women, ages 55-76y (mean age: 66 ± 6y), with LDL-cholesterol levels >130 mg/dL (mean=161 ± 8 mg/dL) and not on cholesterol-lowering medications, received simvastatin (80 mg/day) for 12 weeks.
Procedures:	At baseline, participants had blood drawn for measurements of lipids and other blood chemistries, as well as a short physical exam. They then underwent a series of exercise tests over 2 days (separated by 1-2 days), including a maximal exercise stress test, maximal strength test, an endurance test, tests of muscular power and muscular endurance, and cycling at sub-maximal intensity for measures of oxygen uptake kinetics. Twenty-four hours after the completion of the exercise testing, blood was drawn to measure creatine kinase, a marker of muscle breakdown and participants were started on statin treatment. An additional blood draw was taken 4-weeks into the treatment period to monitor any changes in liver function. Myalgia symptoms were monitored every 4-weeks. After 12-weeks of statin treatment, all baseline testing procedures were repeated.
Results:	As expected, statin treatment resulted in significant decreases in LDL- and total-cholesterol levels with no changes in HDL-C or triglyceride levels. However, there were no significant changes in aerobic capacity, endurance, oxygen kinetics or any of the measures of muscular function in response to the 12-week treatment. CK levels at rest were significantly higher at 12-weeks but remained within normal ranges. No participant reported symptoms of myalgia, cramps, or weakness at any of the assessments.
Conclusion:	High-dose simvastatin for 12 weeks did not result in myalgia symptoms or impaired exercise capacity in a sample of older individuals. These data suggest that the decreases in intramuscular CoQ10 that have previously been observed in response to high dose statin treatment, may not be clinically relevant in terms of diminishing exercise capacity in individuals who do not experience myalgia symptoms.

Presented: American College of Sport Medicine Annual Meeting (New Orleans, June 2007)