Mitochondrial abnormalities contribute to muscle weakness in a Dnajb6 deficient zebrafish model.

Autor:	McKaige EA; School of Biological Sciences Monash University, 25 Rainforest Walk, Clayton, VIC 3800, Australia., Lee C; School of Biological Sciences Monash University, 25 Rainforest Walk, Clayton, VIC 3800, Australia., Calcinotto V; School of Biological Sciences Monash University, 25 Rainforest Walk, Clayton, VIC 3800, Australia., Giri S; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia., Crawford S; Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, 15 Innovation Walk, Clayton, VIC 3800, Australia., McGrath MJ; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia., Ramm G; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia.; Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, 15 Innovation Walk, Clayton, VIC 3800, Australia., Bryson-Richardson RJ; School of Biological Sciences Monash University, 25 Rainforest Walk, Clayton, VIC 3800, Australia.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2024 Jul 06; Vol. 33 (14), pp. 1195-1206.
DOI:	10.1093/hmg/ddae061
Abstrakt:	Mutations in DNAJB6 are a well-established cause of limb girdle muscular dystrophy type D1 (LGMD D1). Patients with LGMD D1 develop progressive muscle weakness with histology showing fibre damage, autophagic vacuoles, and aggregates. Whilst there are many reports of LGMD D1 patients, the role of DNAJB6 in the muscle is still unclear. In this study, we developed a loss of function zebrafish model in order to investigate the role of Dnajb6. Using a double dnajb6a and dnajb6b mutant model, we show that loss of Dnajb6 leads to a late onset muscle weakness. Interestingly, we find that adult fish lacking Dnajb6 do not have autophagy or myofibril defects, however, they do show mitochondrial changes and damage. This study demonstrates that loss of Dnajb6 causes mitochondrial defects and suggests that this contributes to muscle weakness in LGMD D1. These findings expand our knowledge of the role of Dnajb6 in the muscle and provides a model to screen novel therapies for LGMD D1. (© The Author(s) 2024. Published by Oxford University Press.)
Databáze:	MEDLINE
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