Autophagy signaling in skeletal muscle of infarcted rats

PLoS One. 2014 Jan 10;9(1):e85820. doi: 10.1371/journal.pone.0085820. eCollection 2014.

Abstract

Background: Heart 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 findings: Wistar 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.

Conclusions: Altogether 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy* / genetics
  • Biomarkers
  • Cathepsin L / metabolism
  • Echocardiography
  • Gene Expression Regulation
  • Male
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism
  • Muscular Atrophy / etiology*
  • Muscular Atrophy / metabolism*
  • Muscular Atrophy / pathology
  • Myocardial Infarction / complications*
  • Myocardial Infarction / diagnosis
  • Myocardial Infarction / physiopathology
  • Oxidative Stress
  • Physical Conditioning, Animal
  • Rats
  • Signal Transduction*
  • Transcriptome

Substances

  • Biomarkers
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Cathepsin L

Grant support

PRJ held a master degree scholarship from Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil (FAPESP #2010/14567-4). PCB holds grants from FAPESP (#2010/50048-1) and Conselho Nacional de Pesquisa e Desenvolvimento (CNPq #302201/2011-4). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.