Abstract
BackgroundHeart failure (HF)-induced skeletal muscle atrophy is often associated to exercise intolerance and poor prognosis. Better understanding of the molecular mechanisms underlying HF-induced muscle atrophy may contribute to the development of pharmacological strategies to prevent or treat such condition. It has been shown that autophagy-lysosome system is an important mechanism for maintenance of muscle mass. However, its role in HF-induced myopathy has not been addressed yet. Therefore, the aim of the present study was to evaluate autophagy signaling in myocardial infarction (MI)-induced muscle atrophy in rats.Methods/Principal FindingsWistar rats underwent MI or Sham surgeries, and after 12 weeks were submitted to echocardiography, exercise tolerance and histology evaluations. Cathepsin L activity and expression of autophagy-related genes and proteins were assessed in soleus and plantaris muscles by fluorimetric assay, qRT-PCR and immunoblotting, respectively. MI rats displayed exercise intolerance, left ventricular dysfunction and dilation, thereby suggesting the presence of HF. The key findings of the present study were: a) upregulation of autophagy-related genes (GABARAPL1, ATG7, BNIP3, CTSL1 and LAMP2) was observed only in plantaris while muscle atrophy was observed in both soleus and plantaris muscles, and b) Cathepsin L activity, Bnip3 and Fis1 protein levels, and levels of lipid hydroperoxides were increased specifically in plantaris muscle of MI rats.ConclusionsAltogether our results provide evidence for autophagy signaling regulation in HF-induced plantaris atrophy but not soleus atrophy. Therefore, autophagy-lysosome system is differentially regulated in atrophic muscles comprising different fiber-types and metabolic characteristics.
Highlights
Cardiovascular diseases (CVD) are leading causes of death worldwide and pose significant burden to financial and public health systems [1]
CVD commonly progress to heart failure (HF), which is a complex syndrome with poor prognosis characterized by severe cardiac dysfunction, dyspnea, exercise intolerance and fluid retention, severely affecting quality of life and lifespan [3]
Previous studies identified that exercise capacity correlates poorly with cardiac hemodynamic variables in Heart failure (HF) patients, while a much stronger association is found with skeletal muscle parameters, such as peripheral blood flow, muscle metabolism and mass [4,5,6,7,8]
Summary
Cardiovascular diseases (CVD) are leading causes of death worldwide and pose significant burden to financial and public health systems [1]. It has been shown that skeletal muscle catabolism is favored over anabolism in patients with chronic diseases, which occurs due to changes in inflammatory cytokines levels, redox homeostasis, nutrient availability, calcium handling, physical activity levels and growth factors [10,11,12,13,14,15]. These alterations contribute to boosted protein breakdown, mainly by two highly conserved proteolytic mechanisms, the ubiquitin-proteasome and the autophagy-lysosome systems [16]. The aim of the present study was to evaluate autophagy signaling in myocardial infarction (MI)-induced muscle atrophy in rats
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