Abstract
Abstract 16948: TXLNB is Necessary for Physiological Hypertrophy During Cardiac Aging
Circulation (New York, N.Y.), Vol.138(Suppl_1 Suppl 1), pp.A16948-A16948
11/06/2018
Abstract
Cardiac aging in mice and humans is associated with cardiac hypertrophy, fibrosis, diastolic dysfunction, and a reduced ability to adapt to stress. Recent evidence suggests that cardiac proteostasis - the coordinated regulation of protein synthesis, repair, and degradation mechanisms - is dysregulated during cardiac aging and contributes to cardiac structural and functional deficits, but the underlying molecular mechanisms are unknown. In recent work, we identified beta-taxilin (TXLNB) as a cardiac-enriched protein that regulates cardiomyocyte proteostasis. Overexpression of TXLNB in neonatal rat cardiomyocytes increased protein synthesis, decreased ubiquitination, increased proteasome activity, and increased autophagy. In addition, TXLNB-knockout (TXLNB-KO) mice generated by CRISPR/Cas9 exhibited altered cardiac proteasome activities (Fig. 1Adecreased 26Sβ5 activity (p=0.025, n=8), increased 26Sβ1 activity (p=0.13, n=8), and accumulate ubiquitinated proteins (Fig. 1B). Despite this profound proteasomal insufficiency, TXLNB-KO mice develop normal cardiac structure and function (at 12 weeks of age) and show appropriate hypertrophic responses to pressure overload via transverse aortic constriction. This suggests that TXLNB is not required for cardiac development or cardiac hypertrophy in young mice. We therefore initiated follow-up studies in 3, 6, 10, and 24 week-old mice to evaluate the role of TXLNB in aging-related cardiac hypertrophy. In these mice, there was no significant difference in body weight or tibia length based on genotype; however, between 10-24 months of age, TXLNB-KO mice did not show the typical increase in heart size observed in WT mice (Fig.1C, 10 months, p=0.023, n=7; 24 months, p=0.026, n=3-4). This suggests that TXLNB is necessary for adaptive cardiac remodeling that occurs during aging. Ongoing work will establish if aged TXLNB-KO mice have decreased cardiac function or an impaired adaptation to cardiac stress.
Details
- Title: Subtitle
- Abstract 16948: TXLNB is Necessary for Physiological Hypertrophy During Cardiac Aging
- Creators
- Jared McLendon - Internal Medicine, Univ of Iowa, Iowa City, IAXiaoming ZhangNathan WitmerGabrielle AbouassalyColleen SteinRyan Boudreau
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.138(Suppl_1 Suppl 1), pp.A16948-A16948
- Publisher
- by the American College of Cardiology Foundation and the American Heart Association, Inc
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/06/2018
- Academic Unit
- Cardiovascular Medicine; Internal Medicine; Iowa Neuroscience Institute
- Record Identifier
- 9984071634902771
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