Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling

Megan T. Quintana, Traci L. Parry, Jun He, Cecelia C. Yates, Tatiana N. Sidorova, Katherine T. Murray, James R. Bain, Christopher B. Newgard, Michael J. Muehlbauer, Samuel C. Eaton, Akinori Hishiya, Shin Takayama, Monte Willis

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The Bcl2-associated anthanogene (BAG) 3 protein is a member of the BAG family of cochaperones, which supports multiple critical cellular processes, including critical structural roles supporting desmin and interactions with heat shock proteins and ubiquitin ligases intimately involved in protein quality control. The missense mutation P209L in exon 3 results in a primarily cardiac phenotype leading to skeletal muscle and cardiac complications. At least 10 other Bag3 mutations have been reported, nine resulting in a dilated cardiomyopathy for which no specific therapy is available. We generated αMHC-human Bag3 P209L transgenic mice and characterized the progressive cardiac phenotype in vivo to investigate its utility in modeling human disease, understand the underlying molecular mechanisms, and identify potential therapeutic targets. We identified a progressive heart failure by echocardiography and Doppler analysis and the presence of pre-amyloid oligomers at 1 year. Paralleling the pathogenesis of neurodegenerative diseases (eg, Parkinson disease), pre-amyloid oligomers–associated alterations in cardiac mitochondrial dynamics, haploinsufficiency of wild-type BAG3, and activation of p38 signaling were identified. Unexpectedly, increased numbers of activated cardiac fibroblasts were identified in Bag3 P209L Tg+ hearts without increased fibrosis. Together, these findings point to a previously undescribed therapeutic target that may have application to mutation-induced myofibrillar myopathies as well as other common causes of heart failure that commonly harbor misfolded proteins.

Original languageEnglish (US)
Pages (from-to)1989-2007
Number of pages19
JournalAmerican Journal of Pathology
Volume186
Issue number8
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

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Haploinsufficiency
Cardiac Myocytes
Amyloid
Heart Failure
Mitochondrial Dynamics
Phenotype
Mutation
Proteins
Desmin
Doppler Echocardiography
Dilated Cardiomyopathy
Missense Mutation
Ligases
Ubiquitin
Heat-Shock Proteins
Neurodegenerative Diseases
Quality Control
Transgenic Mice
Parkinson Disease
Exons

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling. / Quintana, Megan T.; Parry, Traci L.; He, Jun; Yates, Cecelia C.; Sidorova, Tatiana N.; Murray, Katherine T.; Bain, James R.; Newgard, Christopher B.; Muehlbauer, Michael J.; Eaton, Samuel C.; Hishiya, Akinori; Takayama, Shin; Willis, Monte.

In: American Journal of Pathology, Vol. 186, No. 8, 01.08.2016, p. 1989-2007.

Research output: Contribution to journalArticle

Quintana, MT, Parry, TL, He, J, Yates, CC, Sidorova, TN, Murray, KT, Bain, JR, Newgard, CB, Muehlbauer, MJ, Eaton, SC, Hishiya, A, Takayama, S & Willis, M 2016, 'Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling', American Journal of Pathology, vol. 186, no. 8, pp. 1989-2007. https://doi.org/10.1016/j.ajpath.2016.03.017
Quintana, Megan T. ; Parry, Traci L. ; He, Jun ; Yates, Cecelia C. ; Sidorova, Tatiana N. ; Murray, Katherine T. ; Bain, James R. ; Newgard, Christopher B. ; Muehlbauer, Michael J. ; Eaton, Samuel C. ; Hishiya, Akinori ; Takayama, Shin ; Willis, Monte. / Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling. In: American Journal of Pathology. 2016 ; Vol. 186, No. 8. pp. 1989-2007.
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