In response to eccentric exercise, women experienced greater immediate strength loss than men and were more likely to be high responders for immediate strength loss; men experienced greater serum CK activity than women and were more likely to be high responders for increased serum CK. Although the explanation for high responders to eccentric exercise remains unknown, we have shown that there are sex-specific differences in CK and strength-loss response after eccentric exercise.
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are generally well-tolerated lipid-lowering drugs. However, they are associated with myopathy, and incidence rates of muscle-related complaints predicted from clinical trials may underestimate rate of occurrence of these side effects in clinical practice. The development of a standardized system for description and documentation of statin-associated myopathy that includes the entire spectrum of muscle complaints would provide valuable data for researchers and clinicians seeking to better understand statin-induced muscle complaints. Among the risk factors for myopathy are polypharmacy, high-dose statin treatment, aging, and diabetes. The etiology of statin-induced myopathy is not well understood, but potential contributing mechanisms include decreases in mevalonate pathway products, mitochondrial dysfunction, alterations in gene expression related to apoptosis and protein degradation, and genetic predisposition.
Aim
The 3-hydroxy-3methylgutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most effective prescribed drugs for lowering serum cholesterol; however, although statins are extremely safe medications and have brought significant benefits to patients with hypercholesterolemia, they have been shown to produce myalgia, cramps, exercise intolerance and fatigue. The aim of the study was to investigate the molecular mechanisms that may mediate statin myopathy.
Methods
We used DNA microarray analysis to examine the changes in gene expression profiles induced by 1 hour and 6 hours of statin treatment on differentiated C2C12 myotubes. Four genes were selected for analysis at the protein level using Western blot analysis on myotubes treated with statin with or without additional mechanical stretching.
Results
Eighty-five genes exhibited more than a 2-fold up- or down-regulation in expression, of which 46 have known biological functions related primarily to transmembrane transport, signal transduction, cell growth/maintenance, protein metabolism, or apoptosis. At protein level, three of the four proteins were induced (Adrb1, Socs4 and Cflar) and one was repressed (Birc4). Changes in protein expression largely mirrored the changes in their corresponding transcripts, although the fold-change was less dramatic. The addition of imposed muscle fiber stretching did not exacerbate the expression of these genes at the protein level with the exception of Cflar, a pro-apoptotic protein.
Conclusion
These data suggested that alterations in the expressions of some statin-regulated genes could be causative factors for statin toxicity in muscle. Repression of the anti-apoptosis gene (Birc4) and activation of the pro-apoptosis gene (Cflar) indicated that cell death may play an important role in statin-induced myopathy.
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