Exercise mitigates reductive stress-induced cardiac remodeling in mice
Arun Jyothidasan,
Sini Sunny,
Asokan Devarajan,
Aniqa Sayed,
John Kofi Afortude,
Brian Dalley,
Vivek Nanda,
Steven Pogwizd,
Silvio H. Litovsky,
Joel D. Trinity,
Matthew Might,
Namakkal S. Rajasekaran
Affiliations
Arun Jyothidasan
Cardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology/Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
Sini Sunny
Cardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology/Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
Asokan Devarajan
Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
Aniqa Sayed
Cardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology/Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
John Kofi Afortude
Cardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology/Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
Brian Dalley
Department of Medicine, University of Utah, School of Medicine, Salt Lake City, UT, USA
Vivek Nanda
Cardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology/Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
Steven Pogwizd
Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
Silvio H. Litovsky
Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
Joel D. Trinity
Department of Medicine, University of Utah, School of Medicine, Salt Lake City, UT, USA
Matthew Might
Hugh Kaul Precision Medicine Institute, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
Namakkal S. Rajasekaran
Cardiac Aging & Redox Signaling Laboratory, Molecular and Cellular Pathology, Department of Pathology/Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Medicine, University of Utah, School of Medicine, Salt Lake City, UT, USA; Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Corresponding author. Cardiac Aging & Redox Signaling Laboratory, Center for Free Radical Biology, Division of Molecular & Cellular Pathology, Department of Pathology | The University of Alabama at Birmingham, PBMR Room 533|901 19th Street South, Birmingham, AL, 35294, USA.
The endoplasmic reticulum (ER) regulates protein folding and maintains proteostasis in cells. We observed that the ER transcriptome is impaired during chronic reductive stress (RS) in cardiomyocytes. Here, we hypothesized that a prolonged moderate treadmill exercise mitigates the RS-induced ER dysfunction and cardiac remodeling in cardiac-specific constitutively active Nrf2 mice (CaNrf2-TG). RNA sequencing showed notable alterations in the ER transcriptome of TG hearts at 4, 12, and 24 weeks (16, 28, and 35 genes, respectively). Notably, the downregulation of ER genes was significant at 12 weeks, and further pronounced at 24 weeks, at which the cardiac pathology is evident. We also observed increased levels of ubiquitinated proteins in CaNrf2-TG hearts across all ages, along with VCP, a marker of ERAD function, at 24 weeks. These findings indicate that constitutive Nrf2 activation and RS impair protein-folding activity and augments ERAD function over time. Exercise intervention for 20 weeks (beginning at 6 weeks of age), reduced cardiomyocyte hypertrophy (from 448 μm2 to 280 μm2) in TG mice, through adaptive remodeling, and preserved the cardiac function. However, while exercise did not influence antioxidants or ER stress protein levels, it significantly improved ERAD function and autophagy flux (LC-I to LC-II) in the TG-EXE hearts. Collectively, our findings underscore the prophylactic potential of exercise in mitigating RS-associated pathology, highlighting its essential role in maintaining cellular proteostasis through ER-independent mechanisms.
