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Mitochondrial abnormalities contribute to muscle weakness in a Dnajb6 deficient zebrafish model
Emily A McKaige1, Clara Lee1, Vanessa Calcinotto1
1School of Biological Sciences Monash University, 25 Rainforest Walk, Clayton, VIC 3800, Australia.
Abstract:
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.
Insights
Loss of DNAJB6 causes late-onset muscle weakness in zebrafish, linked to mitochondrial damage. This finding offers a new model for studying limb girdle muscular dystrophy type D1 (LGMD D1) and developing therapies.
Area of Science:
- Muscle biology
- Genetics
- Zebrafish models
Background:
- Mutations in DNAJB6 are a known cause of limb girdle muscular dystrophy type D1 (LGMD D1).
- LGMD D1 patients exhibit progressive muscle weakness, fiber damage, autophagic vacuoles, and aggregates.
- The precise role of DNAJB6 in muscle function remains incompletely understood.
Purpose of the Study:
- To investigate the function of Dnajb6 in muscle using a loss-of-function zebrafish model.
- To elucidate the molecular mechanisms underlying muscle weakness in LGMD D1.
Main Methods:
- Development of a double dnajb6a and dnajb6b mutant zebrafish model.
- Analysis of muscle histology, autophagy, myofibril integrity, and mitochondrial function in mutant fish.
Main Results:
- Loss of Dnajb6 function in zebrafish results in late-onset muscle weakness.
- Adult dnajb6 mutant fish do not display autophagy or myofibril defects.
- Mitochondrial changes and damage were observed in adult fish lacking Dnajb6.
Conclusions:
- Loss of Dnajb6 leads to mitochondrial defects, contributing to muscle weakness in LGMD D1.
- This study provides a valuable zebrafish model for screening potential therapies for LGMD D1.
