Center for Advanced Cardiac Care, Department of Medicine, Division of Cardiology, Columbia University Medical Center, 622 West 168th Street, PH 10, Room 203, New York, NY, 10032, USA.
J Cachexia Sarcopenia Muscle. 2014 Dec;5(4):297-305. doi: 10.1007/s13539-014-0155-9. Epub 2014 Aug 7.
Skeletal muscle dysfunction in patients with heart failure (HF) has been linked to impaired growth hormone (GH)/insulin-like growth factor (IGF)-1 signaling. We hypothesized that ventricular assist device (VAD) implantation reverses GH/IGF-1 axis dysfunction and improves muscle metabolism in HF.
Blood and rectus abdominis muscle samples were collected during VAD implantation and explantation from patients with HF and controls. Clinical data were obtained from medical records, biomarkers measured by enzyme-linked immunosorbent assay (ELISA), and gene expression analyzed by reverse transcription and real-time polymerase chain reaction (RT-PCR). Grip strength was assessed by dynamometry. Oxidative capacity was measured using oleate oxidation rates. Muscle fiber type and size were assessed by histology.
Elevated GH (0.27 ± 0.27 versus 3.6 ± 7.7 ng/ml in HF; p = 0.0002) and lower IGF-1 and insulin-like growth factor binding protein (IGFBP)-3 were found in HF (IGF-1, 144 ± 41 versus 74 ± 45 ng/ml in HF, p < 0.05; and IGFBP-3, 3,880 ± 934 versus 1,935 ± 862 ng/ml in HF, p = 0.05). The GH/IGF-1 ratio, a marker of GH resistance, was elevated in HF (0.002 ± 0.002 versus 0.048 ± 0.1 pre-VAD; p < 0.0039). After VAD support, skeletal muscle expression of IGF-1 and IGFBP-3 increased (10-fold and 5-fold, respectively; p < 0.05) accompanied by enhanced oxidative gene expression (CD36, CPT1, and PGC1α) and increased oxidation rates (+1.37-fold; p < 0.05). Further, VAD implantation increased the oxidative muscle fiber proportion (38 versus 54 %, p = 0.031), fiber cross-sectional area (CSA) (1,005 ± 668 versus 1,240 ± 670 μm(2), p < 0.001), and Akt phosphorylation state in skeletal muscle. Finally, hand grip strength increased 26.5 ± 27.5 % at 180 days on-VAD (p < 0.05 versus baseline).
Our data demonstrate that VAD implantation corrects GH/IGF-1 signaling, improves muscle structure and function, and enhances oxidative muscle metabolism in patients with advanced HF.
心力衰竭（HF）患者的骨骼肌功能障碍与生长激素（GH）/胰岛素样生长因子（IGF）-1 信号转导受损有关。我们假设心室辅助装置（VAD）植入可逆转 GH/IGF-1 轴功能障碍并改善 HF 患者的肌肉代谢。
在 HF 患者和对照组的 VAD 植入和取出过程中采集血液和腹直肌样本。临床数据来自病历，通过酶联免疫吸附试验（ELISA）测量生物标志物，通过逆转录和实时聚合酶链反应（RT-PCR）分析基因表达。通过测力法评估握力。使用油酸盐氧化率测量氧化能力。通过组织学评估肌肉纤维类型和大小。
HF 患者中 GH 升高（0.27±0.27 与 3.6±7.7 ng/ml；p=0.0002），IGF-1 和胰岛素样生长因子结合蛋白（IGFBP）-3 降低（IGF-1，144±41 与 74±45 ng/ml；p<0.05；IGFBP-3，3880±934 与 1935±862 ng/ml；p=0.05）。GH/IGF-1 比值升高，表明 GH 抵抗（HF 中为 0.002±0.002，VAD 前为 0.048±0.1；p<0.0039）。VAD 支持后，骨骼肌中 IGF-1 和 IGFBP-3 的表达增加（分别增加 10 倍和 5 倍；p<0.05），同时氧化基因表达增强（CD36、CPT1 和 PGC1α），氧化速率增加（增加 1.37 倍；p<0.05）。此外，VAD 植入增加了氧化肌纤维比例（38%与 54%；p=0.031）、纤维横截面积（CSA）（1005±668 与 1240±670 μm(2)；p<0.001）和骨骼肌中 Akt 的磷酸化状态。最后，在 VAD 上 180 天时，手握力增加了 26.5±27.5%（与基线相比；p<0.05）。
我们的数据表明，VAD 植入可纠正 GH/IGF-1 信号转导，改善 HF 患者的肌肉结构和功能，并增强肌肉的氧化代谢。
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