Dataset Information

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

ACCESS DATA

Publications

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

Sunitha Balaraju B Gayathri Narayanappa N Kumar Manish M Keshava Prasad Thottethodi Subrahmanya TS Nalini Atchayaram A Padmanabhan Balasundaram B Srinivas Bharath Muchukunte Mukunda MM

Journal of neurochemistry 20160516 1

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; ...[more]

PMID: 27015874

Similar Datasets

Project description:Skeletal muscle mitochondrial dysfunction is secondary to T2DM and can be improved by long-term regular exercise training Mitochondrial dysfunction has long been implicated to play a causative role in development of type 2 diabetes (T2DM). However, a growing number of recent studies provide data that mitochondrial dysfunction is a consequence of T2DM development. The aim of our study is to clarify in further detail the causal role of mitochondrial dysfunction in T2DM by a comprehensive ex vivo analysis of mitochondrial function combined with global gene expression analysis in muscle of pre-diabetic newly diagnosed untreated T2DM subjects and long-standing insulin treated T2DM subjects compared with age- and BMI-matched controls. In addition, we assessed the impact of long-term interval exercise training on physical activity performance, mitochondrial function and glycemic control in long-standing insulin-treated T2DM subjects. Ex vivo mitochondrial density, quality and functioning was comparable between pre-diabetic subjects and matched controls, however, gene expression analysis showed a switch from carbohydrate toward lipids as energy source in pre-diabetes subjects. In contrast, long-term insulin treated T2DM subjects had slightly decreased mitochondrial density and ex vivo function. Expression of Krebs cycle and OXPHOS related genes were decreased, indicating a decreased capacity to use lipids as an energy source. The insulin-treated T2DM subjects had a lower physical activity level than pre-diabetic and normoglycemic subjects. A 52 weeks exercise training of these subjects increased submaximal oxidative efficiency, increased in vivo PCr recovery rate, as well as mildly increased in vitro mitochondrial function. Gene expression of β-oxidation, Krebs cycle and OXPHOS-related genes was increased. Our data demonstrate that mitochondrial dysfunction is rather a consequence than a causative factor in T2DM development as it was only detected in overt diabetes and not in early diabetes. Regular exercise training stabilized exogenous insulin requirement and improved mitochondrial functioning, fatty acid oxidation and general physical work load capacity in long-standing insulin-treated T2DM subjects. As such, the present study shows for the first time that long-term exercise interventions are beneficial in this group of complex diabetes patient and may prevent further metabolic deterioration. Insulin-treated T2DM subjects before and after 52 weeks of exercise training (T2DM_0 and T2DM_52), normoglycemic controls (NGT) and pre-diabetes subjects (IGT) and were selected. RNA was extracted from skeletal muscle biopsies and hybridized on Affymetrix microarrays.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure