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Published on: February 10, 2013
Exercise mitigates reductive stress-induced cardiac remodeling in mice
Arun Jyothidasan1, Sini Sunny1, Asokan Devarajan2
1Cardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology/Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
Prolonged treadmill exercise mitigated endoplasmic reticulum (ER) dysfunction and cardiac remodeling in mice with constitutive Nrf2 activation. Exercise improved ER-associated degradation (ERAD) function and autophagy flux, highlighting its protective role against reductive stress-associated pathology.
Area of Science:
- Cardiovascular Biology
- Cellular Proteostasis
- Exercise Physiology
Background:
- The endoplasmic reticulum (ER) is crucial for protein folding and cellular proteostasis.
- Chronic reductive stress (RS) impairs ER function in cardiomyocytes.
- Constitutive Nrf2 activation in cardiac-specific Nrf2 transgenic (CaNrf2-TG) mice exacerbates ER transcriptome alterations and protein aggregation.
Purpose of the Study:
- To investigate if prolonged moderate treadmill exercise can mitigate RS-induced ER dysfunction and cardiac remodeling in CaNrf2-TG mice.
- To elucidate the effects of exercise on ER transcriptome, protein folding, ER-associated degradation (ERAD), and autophagy.
- To assess the prophylactic potential of exercise in maintaining cardiac function under chronic RS.
Main Methods:
- Utilized RNA sequencing to analyze ER transcriptome alterations in CaNrf2-TG hearts at various ages.
- Quantified ubiquitinated proteins and VCP levels as markers of ERAD function.
- Implemented a 20-week treadmill exercise intervention starting at 6 weeks of age.
- Assessed cardiomyocyte hypertrophy, cardiac function, antioxidant levels, ER stress markers, ERAD function, and autophagy flux (LC-I to LC-II).
Main Results:
- CaNrf2-TG hearts showed significant downregulation of ER genes and increased ubiquitinated proteins over time, indicating impaired protein folding and augmented ERAD.
- Exercise intervention reduced cardiomyocyte hypertrophy and preserved cardiac function in TG mice.
- Exercise did not alter antioxidant or ER stress protein levels but significantly improved ERAD function and autophagy flux in TG-EXE hearts.
Conclusions:
- Constitutive Nrf2 activation combined with RS leads to ER dysfunction and cardiac pathology.
- Exercise demonstrates prophylactic potential against RS-associated cardiac pathology.
- Exercise mitigates cardiac remodeling and preserves function, potentially through ER-independent mechanisms enhancing ERAD and autophagy.
