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Am J Pathol. 2020 Mar;190(3):554-562. doi: 10.1016/j.ajpath.2019.11.005. Epub 2020 Jan 14.

BAG3P215L/KO Mice as a Model of BAG3P209L Myofibrillar Myopathy.

Author information

1
Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
2
Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
3
Cone Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
4
School of Biological Sciences, Monash University, Melbourne, Australia.
5
Centre de Recherche sur le Cancer, l'Université Laval, Québec, Quebec, Canada; Oncology Axis, Centre de Recherche du Centre Hospitalier Universitaire (CHU), Québec-Université Laval, Québec, Quebec, Canada; Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, l'Université Laval, Québec, Quebec, Canada.
6
Rare Neurological Diseases Group, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
7
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
8
Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. Electronic address: bernard.brais@mcgill.ca.

Abstract

BCL-2-associated athanogene 3 (BAG3) is a co-chaperone to heat shock proteins important in degrading misfolded proteins through chaperone-assisted selective autophagy. The recurrent dominant BAG3-P209L mutation results in a severe childhood-onset myofibrillar myopathy (MFM) associated with progressive muscle weakness, cardiomyopathy, and respiratory failure. Because a homozygous knock-in (KI) strain for the mP215L mutation homologous to the human P209L mutation did not have a gross phenotype, compound heterozygote knockout (KO) and KI mP215L mice were generated to establish whether further reduction in BAG3 expression would lead to a phenotype. The KI/KO mice have a significant decrease in voluntary movement compared with wild-type and KI/KI mice in the open field starting at 7 months. The KI/KI and KI/KO mice both have significantly smaller muscle fiber cross-sectional area. However, only the KI/KO mice have clear skeletal muscle histologic changes in MFM. As in patient muscle, there are increased levels of BAG3-interacting proteins, such as p62, heat shock protein B8, and αB-crystallin. The KI/KO mP215L strain is the first murine model of BAG3 myopathy that resembles the human skeletal muscle pathologic features. The results support the hypothesis that the pathologic development of MFM requires a significant decrease in BAG3 protein level and not only a gain of function caused by the dominant missense mutation.

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