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Keywords:

  • ATG5;
  • autophagy;
  • Beclin 1;
  • clathrin;
  • human myopathy;
  • LC3;
  • rimmed vacuoles;
  • SMI-31

Aims

Sporadic inclusion body myositis (s-IBM) is characterized by rimmed vacuole formation and misfolded protein accumulation. Intracellular protein aggregates are cleared by autophagy. When autophagy is blocked aggregates accumulate, resulting in abnormal rimmed vacuole formation. This study investigated the autophagy–lysosome pathway contribution to rimmed vacuole accumulation.

Methods

Autophagy was studied in muscle biopsy specimens obtained from eleven s-IBM patients, one suspected hereditary IBM patient, nine patients with other inflammatory myopathies and nine non-myopathic patients as controls. The analysis employed morphometric methods applied to immunohistochemistry using the endosome marker Clathrin, essential proteins of the autophagic cascade such as AuTophaGy-related protein ATG5, splicing variants of microtubule-associated protein light chain 3a (LC3a) and LC3b, compared with Beclin 1, the major autophagy regulator of both the initiation phase and late endosome/lysosome fusion of the autophagy–lysosome pathway.

Results

In muscle biopsies of s-IBM patients, an increased expression of Clathrin, ATG5, LC3a, LC3b and Beclin 1 was shown. Moreover, the inflammatory components of the disease, essentially lymphocytes, were preferentially distributed around the Beclin 1+ myofibres. These affected myofibres also showed a moderate sarcoplasmic accumulation of SMI-31+ phospho-tau paired helical filaments.

Conclusion

The overexpression of autophagy markers linked to the decreased clearance of misfolded proteins, including SMI-31, and rimmed vacuoles accumulation may exhaust cellular resources and lead to cell death.