- 作者：Holly R. Middlekauff ; Chris Vigna ; M. Anthony Verity ; Gregg C. Fonarow ; Tamara B. Horwich ; Michele A. Hamilton ; Perry Shieh ; A. Russell Tupling
- 关键词：Exercise intolerance ; sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a ; sympathetic nerve activity ; oxidative stress
- 刊名：Journal of Cardiac Failure
- 出版年：2012
- 出版时间：September, 2012
- 年：2012
- 卷：18
- 期：9
- 页码：724-733
- 全文大小：601 K
Background
In the failing human heart, abnormalities of Ca2+ cycling have been described, but there is scant knowledge about Ca2+ handling in the skeletal muscle of humans with heart failure (HF). We tested the hypothesis that in humans with HF, Ca2+ cycling proteins in skeletal muscle are abnormal.Methods and Results
Ten advanced HF patients (50.4?¡À?3.7 years), and 9 age-matched controls underwent vastus lateralis biopsy. Western blot analysis showed that sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a, which is responsible for Ca2+ sequestration into the sarcoplasmic reticulum(SR), was lower in HF versus controls (4.8?¡À?0.5 vs 7.5 ¡À 0.8 AU, P?=?.01). Although phospholamban (PLN), which inhibits SERCA2a, was not different in HF versus controls, phosphorylation (SER16 site) of PLN, which relieves this inhibition, was reduced (0.8 ¡À 0.1 vs 3.9 ¡À 0.9 AU, P?=?.004). Dihydropyridine receptors were reduced in HF, (2.1 ¡À 0.4 vs 3.6 ¡À 0.5 AU, P?=?.04). We tested the hypothesis that these abnormalities of Ca2+ handling protein content and regulation were due to increased oxidative stress, but oxygen radical scavenger proteins were not elevated in the skeletal muscle of HF patients.
Conclusion
In chronic HF, marked abnormalities of Ca2+ handling proteins are present in skeletal muscle, which mirror those in failing heart tissue. This suggests a common mechanism, such as chronic augmentation of sympathetic activity and autophosphorylation of Ca2+-calmodulin-dependent-protein kinase II.