期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1852, 期 12, 页码 2722-2731出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2015.10.002
关键词
Pulmonary arterial hypertension; Skeletal muscle wasting; Proteolysis; Mitochondrial dysfunction
资金
- Portuguese Foundation for Science and Technology (FCT)
- European Union
- QREN
- FEDER
- COMPETE [PEst-C/QUI/UI0062/2013, Pest-OE/SAU/UI0617/2011, PTDC/DES/114122/2009, FCOMP-01-0124-FEDER-01477]
- Portuguese Foundation for Science and Technology [SFRH/BPD/90010/2012, SFRH/BPD/78259/2011, SFRH/BPD/94312/2013, SFRH/BD/91067/2012]
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/78259/2011, SFRH/BD/91067/2012] Funding Source: FCT
Background: Skeletal muscle wasting contributes to the poor functional status and quality of life of patients with pulmonary arterial hypertension (PAH). The present study aims to characterize the molecular mechanism underlying skeletal muscle wasting in experimental PAH induced by monocrotaline (MCT). Methods: Male Wistar rats were randomly injected with saline solution (CONT; n = 10) or MCI' (MCI': 60 mg/kg, s.c.; n = 15). After 4 weeks of MCI' or vehicle administration, animals were anesthetized and submitted to right ventricular (RV) hemodynamic evaluation. Blood and gastrocnemius samples were collected and stored for analysis. Results: MCT group developed PAH (70% increase in RV peak systolic pressure) RV dysfunction (increased enddiastolic pressure and Tau), and body and muscle wasting (reduction of 20%, 16% and 30% on body weight, gastrocnemius mass and fiber cross sectional area, respectively). Muscle atrophy was associated with a decrease in type I MHC. Circulating (C reactive protein, myostatin and IL-1beta) and local catabolic markers (MAFbx/atrogin-1, protease activity) were increased in MCI' animals, while Akt/mTOR pathway was preserved. Mitochondria isolated from gastrocnemius of MCI' animals showed decreased activity of ATP synthase, lower levels of Tfam, accumulation of oxidatively modified proteins together with reduced levels of paraplegin. Conclusions: Our data suggests an anabolic/catabolic imbalance in gastrocnemius from MCT-induced PAH rats. Accumulation of dysfunctional mitochondria due to the inefficiency of protein quality control systems to eliminate damaged proteins could also contribute to muscle atrophy in PAH. (C) 2015 Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据