Abstract 14128: Abnormalities in Sarcoplasmic Reticulum Ca2+ -Sequestering Proteins in Skeletal Muscle in Humans With Advanced Heart Failure
Background. In chronic HF, the degree of exercise intolerance is not related to cardiac dysfunction, but is largely attributable to abnormalities of the skeletal muscle. Excitation-contraction (E-C) coupling abnormalities in skeletal muscle have been described in animal models of HF, but have not been explored in humans.
Hypothesis. We tested the hypothesis that calcium cycling in skeletal muscle is abnormal in humans with chronic HF, and these abnormalities are attributable to increased reactive oxygen species.
Methods. Skeletal muscle biopsies (vastus lateralis) were obtained from 10 advanced HF patients, (NYHA class II-III, LVEF 25%, mean age 55, 8 men) on stable medications referred for OHT, and 10 age and gender matched healthy controls. Calcium cycling, heat shock protein (HSP), and redox proteins were measured by Western blot analysis.
Results. The major new findings are: 1) SERCA2a, which is responsible for Ca2+ reuptake following contraction, is significantly decreased in HF vs controls, (4.4±0.1 vs 7.5±0.8 AU, p=0.004). 2) Although phospholamban (PLN), an inhibitor of SERCA activity, was not different in HF and controls, phosphorylation (p) of PLN, which reverses PLN inhibition of SERCA, was greatly reduced in HF vs controls (0.7+0.1 vs 3.9+0.9 AU, p=0.006). We next tested the hypothesis that these abnormalities of SERCA levels and regulation were due to increased oxidative stress. However, HSP70 (2.1±0.3 vs 2.6±0.2 AU) and HSP90 (1.03±0.06 vs 1.2±0.07 AU), which are normally up-regulated during oxidative stress, were not elevated in HF, and in fact tended to be lower vs controls. Further, CuZnSOD (1.0±0.2 vs 1.6±0.1 AU, p=0.01), MnSOD (0.6±0.2 vs 1.1±0.1 AU, p=0.06) and catalase (0.6±0.1 vs 1.0±0.1 AU, p=0.007), which have key anti-oxidative roles, were all lower in HF vs controls; reactive nitrotyrosine residues on SERCA, another signal of oxidative stress, were not detectable.
Conclusion. Abnormalities of E-C coupling, including significantly decreased levels of SERCA2a and p-PLN, are present in the resting skeletal muscle of humans with chronic HF. Studies of HSP and oxidative scavenger systems do not support the hypothesis that these E-C coupling abnormalities are attributable to increased resting oxidative stress.
- © 2011 by American Heart Association, Inc.