Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondrial function

J Neurochem. 2016 Jul;138(1):174-91. doi: 10.1111/jnc.13626. Epub 2016 May 16.

Abstract

Muscle diseases are clinically and genetically heterogeneous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from muscle disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n = 43), polymyositis (PM) (inflammatory pathology; n = 24), and distal myopathy with rimmed vacuoles (DMRV) (distal myopathy; n = 31) were analyzed. Mitochondrial damage (ragged blue and COX-deficient fibers) was revealed in dysfy, PM, and DMRV cases by enzyme histochemistry (SDH and COX-SDH), electron microscopy (vacuolation and altered cristae) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three muscle diseases by isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated down-regulation of electron transport chain (ETC) complex subunits, assembly factors and Krebs cycle enzymes. Interestingly, 80 of the under-expressed proteins were common among the three pathologies. Assay of ETC and Krebs cycle enzyme activities validated the MS data. Mitochondrial proteins from muscle pathologies also displayed higher tryptophan (Trp) oxidation and the same was corroborated in the cardiotoxin model. Molecular modeling predicted Trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by morphological changes, altered mitochondrial proteome and protein oxidation, thereby establishing the role of mitochondrial damage in human muscle diseases. We investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from dysferlinopathy (Dysfy), polymyositis (PM), and distal myopathy with rimmed vacuoles (DMRV) displayed morphological and biochemical evidences of mitochondrial dysfunction. Proteomic analysis revealed down-regulation of electron transport chain (ETC) subunits, assembly factors, and tricarboxylic acid (TCA) cycle enzymes, with 80 proteins common among the three pathologies. Mitochondrial proteins from muscle pathologies also displayed higher Trp oxidation that could alter the local structure. Cover image for this issue: doi: 10.1111/jnc.13324.

Keywords: human; mitochondria; muscle; myopathy; proteomics; tryptophan oxidation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Adolescent
  • Adult
  • Aged
  • Aspartate Aminotransferases / metabolism
  • Biopsy
  • Child
  • Citrate (si)-Synthase / metabolism
  • Female
  • Humans
  • Malate Dehydrogenase / metabolism
  • Male
  • Middle Aged
  • Mitochondria / metabolism*
  • Mitochondria / pathology*
  • Mitochondrial Proteins / metabolism*
  • Models, Molecular
  • Multienzyme Complexes / metabolism
  • Muscles / pathology
  • Muscles / ultrastructure*
  • Muscular Diseases / pathology*
  • Superoxide Dismutase / metabolism
  • Tryptophan / metabolism
  • Young Adult

Substances

  • Mitochondrial Proteins
  • Multienzyme Complexes
  • Adenosine Diphosphate
  • Tryptophan
  • Adenosine Triphosphate
  • Malate Dehydrogenase
  • Superoxide Dismutase
  • Citrate (si)-Synthase
  • Aspartate Aminotransferases

Associated data

  • GENBANK/PXD002760