Abstract 237: Antioxidant and Ryanodine Receptor Stabilizing Therapy Prevent Statin-Induced Contractile Dysfunction in a Tissue-Engineered Skeletal Muscle Model
Rationale: Skeletal muscle toxicity of HMG-CoA-reductase inhibitors (statins) ranges from reversible myalgia to irreversible rhabdomyolysis. The underlying molecular mechanisms are not well defined. Tissue engineering models may help to gain insight into these clinically limiting pathologies.
Objective: Here we aimed to model a phenotype of reversible myalgia in vitro to decipher mechanisms that contribute to the early stage of statin toxicity.
Methods and Results: Engineered skeletal muscle (ESM) was generated from rat myoblasts, matrigel, and collagen. Isometrically suspended ESM developed 1.2±0.1 mN force under tetanic field stimulation (80 Hz; 200 mA; n=25). Exposure of ESM to statins for 5 days resulted in a loss of force and increased fatiguability in a concentration dependent manner. Cerivastatin was identified as the most potent statin with respect to muscle toxicity with a TC50 (=50% force reduction) of 0.02 µmol/L (n=25/group). Interestingly, at low cerivastatin concentration (0.01 µmol/L) contractile force of ESM was impaired without obvious signs for structural muscle damage (sarcomeric actin content, CK activity unchanged, n=4). Importantly, ESM dysfunction was fully reversible if challenged with TC50 statin concentrations (n=12-14/group). We reasoned that contractile dysfunction with increased fatiguability resulted from calcium leak via the ryanodine receptor. To test this hypothesis we co-administered S107 and observed a concentration-dependent inhibition of statin-induced force reduction (n=12) and calpain activitiy (a calcium-dependent protease, n=4-6). We further argued that RYR destabilization may have been caused by reactive nitrogen (RNS) and/or reactive oxygen species (ROS). Interestingly, the antioxidant N-acetyl cysteine (1 mmol/L, n=3/group), but not L-NAME (10 mmol/L; NO-synthase inhibition, n=6-12/group) prevented contractile dysfunction.
Conclusion: We utilized a novel tissue engineered skeletal muscle model to decipher mechanisms of statin-induced muscle toxicity and provide evidence for a central role of ryanodine receptor leak, possibly caused by oxidative damage. Our data suggest that antioxidant and RYR-stabilizing approaches may be useful in counteracting statin myopathy.
- © 2012 by American Heart Association, Inc.