Muscle biopsies from human neuromuscular diseases with dystrophic, inflammatory and myopathic pathology reveal common alterations in mitochondrial function

ABSTRACT: Neuromuscular disorders (NMDs) are clinically and genetically heterogenous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin (CTX) mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human NMDs display mitochondrial changes. Muscle biopsies from NMD patients, represented by dystrophic pathology [dysferlinopathy (dysfy); n=43], inflammatory pathology [inflammatory myopathy (IM); n=24] and myopathic pathology [distal myopathy with rimmer vacuoles (DMRV); n=31] were analysed. Mitochondrial damage was revealed in all NMDs by Enzyme histochemistry (SDH and SDH-COX deficiency), electron microscopy (vacuolation and abnormal ultrastructures) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three NMDs by Isobaric tag for relative and absolute quantitation (iTRAQ) labelling 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. Most of the differentially 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 trp oxidation and the same was corroborated in the CTX model. Molecular modelling predicted trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by structural changes, altered mitochondrial proteome and protein oxidation status, thereby establishing the importance of mitochondrial damage in human NMDs.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skeletal Muscle, Muscle Cell

DISEASE(S): Myopathy

SUBMITTER: Srinivas Bharath  

LAB HEAD: M. M. Srinivas Bharath

PROVIDER: PXD002760 | Pride | 2016-04-04

REPOSITORIES: Pride