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Role of the lysosomal/autophagic proteolytic system in skeletal muscle of heart failure animals

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Paulo Roberto Jannig
Total Authors: 1
Document type: Master's Dissertation
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
Defense date:
Examining board members:
Patricia Chakur Brum; Marcelo Saldanha Aoki
Advisor: Patricia Chakur Brum

INTRODUCTION: Heart failure (HF)-induced skeletal muscle atrophy is often associated to exercise intolerance and poor prognosis. Better understanding 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 present study was to evaluate the relative role of the main autophagy-related genes in myocardial infarction (MI)-induced muscle atrophy in rats. METHODS: Wistar rats underwent MI or sham surgeries, and after 12 weeks were submitted to echocardiography, exercise tolerance and histology evaluations. Lysosomal/autophagic proteolytic system components were depicted in skeletal muscle by gene (qRT-PCR) and protein (Western Blotting) expression analysis, and enzymatic activity. RESULTS: MI rats displayed exercise intolerance, left ventricle dysfunction and dilation suggesting the presence of HF. The key finding of the present study is that upregulation of autophagy-related genes (GABARAPL1, ATG7, BNIP3, CTSL1 and LAMP2) was observed only in plantaris while muscle atrophy was depicted in both soleus and plantaris muscles. Furthermore, MI induced higher Bnip3 and Fis1 protein expression, and increased cathepsin L activity and lipid hydroperoxides levels in plantaris muscle. CONCLUSIONS: Altogether our results provide evidence for transcriptional overexpression of autophagy-related genes in MI-induced plantaris atrophy but not soleus atrophy. Therefore, autophagy-related genes are differentially regulated in atrophic muscles comprising different fiber-types and metabolic characteristics. Moreover, changes in lysosomal/autophagic system components in the plantaris muscle indicate increased mitochondrial autophagy (mitophagy), which seems to have contributed to HF-induced plantaris atrophy and exercise intolerance (AU)

FAPESP's process: 10/14567-4 - Role of the lysosomal/autophagic proteolytic system in skeletal muscle of animals with heart failure
Grantee:Paulo Roberto Jannig
Support Opportunities: Scholarships in Brazil - Master