Multiomics analysis of the mdx/mTR mouse model of Duchenne muscular dystrophy.

Autor: Van Pelt DW; Department of Rehabilitation Sciences, College of Health Sciences, University of Kentucky , Lexington, KY, USA., Kharaz YA; Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool , Liverpool, UK., Sarver DC; Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, MI, USA., Eckhardt LR; Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, MI, USA., Dzierzawski JT; Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, MI, USA., Disser NP; Research Institute, Hospital for Special Surgery , New York, NY, USA., Piacentini AN; Research Institute, Hospital for Special Surgery , New York, NY, USA., Comerford E; Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool , Liverpool, UK., McDonagh B; Department of Physiology, School of Medicine, National University of Ireland , Galway, Ireland., Mendias CL; Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, MI, USA.; Research Institute, Hospital for Special Surgery , New York, NY, USA.; Department of Physiology & Biophysics, Weill Cornell Medical College , New York, NY, USA.
Jazyk: angličtina
Zdroj: Connective tissue research [Connect Tissue Res] 2021 Jan; Vol. 62 (1), pp. 24-39. Date of Electronic Publication: 2020 Jul 15.
DOI: 10.1080/03008207.2020.1791103
Abstrakt: Purpose/aim: Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease characterized by extensive muscle weakness. Patients with DMD lack a functional dystrophin protein, which transmits force and organizes the cytoskeleton of skeletal muscle. Multiomic studies have been proposed as a way to obtain novel insight about disease processes from preclinical models, and we used this approach to study pathological changes in dystrophic muscles.
Materials and Methods: We evaluated hindlimb muscles of male mdx/mTR mice, which lack a functional dystrophin protein and have deficits in satellite cell abundance and proliferative capacity. Wild type (WT) C57BL/6 J mice served as controls. Muscle fiber contractility was measured, along with changes in the transcriptome using RNA sequencing, and in the proteome, metabolome, and lipidome using mass spectrometry.
Results: While mdx/mTR mice displayed gross pathological changes and continued cycles of degeneration and regeneration, we found no differences in permeabilized fiber contractility between strains. However, there were numerous changes in the transcriptome and proteome related to protein balance, contractile elements, extracellular matrix, and metabolism. There was only a 53% agreement in fold-change data between the proteome and transcriptome. Numerous changes in markers of skeletal muscle metabolism were observed, with dystrophic muscles exhibiting elevated glycolytic metabolites such as 6-phosphoglycerate, fructose-6-phosphate and glucose-6-phosphate, fructose bisphosphate, phosphorylated hexoses, and phosphoenolpyruvate.
Conclusions: These findings highlight the utility of multiomics in studying muscle disease, and provide additional insight into the pathological changes in dystrophic muscles that might help to indirectly guide evidence-based nutritional or exercise prescription in DMD patients.
Databáze: MEDLINE
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