Adaptation to exercise-induced stress is not dependent on cardiomyocyte α1A-adrenergic receptors

Xenia Kaidonis; Wenxing Niu; Andrea Y Chan; Scott Kesteven; Jianxin Wu; Siiri E Iismaa; Stephen Vatner; Michael Feneley; Robert M Graham

doi:10.1016/j.yjmcc.2021.02.010

Adaptation to exercise-induced stress is not dependent on cardiomyocyte α_1A-adrenergic receptors

J Mol Cell Cardiol. 2021 Jun:155:78-87. doi: 10.1016/j.yjmcc.2021.02.010. Epub 2021 Feb 26.

Authors

Xenia Kaidonis¹, Wenxing Niu², Andrea Y Chan³, Scott Kesteven¹, Jianxin Wu³, Siiri E Iismaa¹, Stephen Vatner⁴, Michael Feneley¹, Robert M Graham⁵

Affiliations

¹ Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; St.Vincent's Clinical School, University of NSW, Kensington, NSW 2052, Australia.
² Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; School of Medical Sciences, University of NSW, Kensington, NSW 2052, Australia.
³ Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia.
⁴ Cardiovascular Research Institute, Dept. of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, NJ 07103, USA.
⁵ Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; St.Vincent's Clinical School, University of NSW, Kensington, NSW 2052, Australia. Electronic address: b.graham@victorchang.edu.au.

PMID: 33647309
DOI: 10.1016/j.yjmcc.2021.02.010

Abstract

The 'fight or flight' response to physiological stress involves sympathetic nervous system activation, catecholamine release and adrenergic receptor stimulation. In the heart, this induces positive inotropy, previously attributed to the β₁-adrenergic receptor subtype. However, the role of the α_1A-adrenergic receptor, which has been suggested to be protective in cardiac pathology, has not been investigated in the setting of physiological stress. To explore this, we developed a tamoxifen-inducible, cardiomyocyte-specific α_1A-adrenergic receptor knock-down mouse model, challenged mice to four weeks of endurance swim training and assessed cardiac outcomes. With 4-OH tamoxifen treatment, expression of the α_1A-adrenergic receptor was knocked down by 80-89%, without any compensatory changes in the expression of other adrenergic receptors, or changes to baseline cardiac structure and function. Swim training caused eccentric hypertrophy, regardless of genotype, demonstrated by an increase in heart weight/tibia length ratio (30% and 22% in vehicle- and tamoxifen-treated animals, respectively) and an increase in left ventricular end diastolic volume (30% and 24% in vehicle- and tamoxifen-treated animals, respectively) without any change in the wall thickness/chamber radius ratio. Consistent with physiological hypertrophy, there was no increase in fetal gene program (Myh7, Nppa, Nppb or Acta1) expression. In response to exercise-induced volume overload, stroke volume (39% and 30% in vehicle- and tamoxifen-treated animals, respectively), cardiac output/tibia length ratio (41% in vehicle-treated animals) and stroke work (61% and 33% in vehicle- and tamoxifen-treated animals, respectively) increased, regardless of genotype. These findings demonstrate that cardiomyocyte α_1A-adrenergic receptors are not necessary for cardiac adaptation to endurance exercise stress and their acute ablation is not deleterious.

Keywords: Cardiac hypertrophy; Exercise; α(1A)-adrenergic receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptation, Physiological*
Animals
Biomarkers
Cardiac Output
Cardiomegaly / diagnosis
Cardiomegaly / etiology
Cardiomegaly / metabolism
Echocardiography, Stress
Genotype
Hemodynamics
Mice
Mice, Knockout
Mice, Transgenic
Models, Animal
Models, Biological*
Myocardial Contraction
Myocytes, Cardiac / metabolism*
Physical Conditioning, Animal*
Receptors, Adrenergic, alpha-1 / genetics
Receptors, Adrenergic, alpha-1 / metabolism*
Stress, Physiological*

Substances

Biomarkers
Receptors, Adrenergic, alpha-1