Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

Abstract

SummaryIncreasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc‐1β knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12‐16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc‐1β−/− (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after β1‐adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc‐1β−/− genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino‐atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc‐1β−/− mice. Moreover, Pgc‐1β−/− mice displayed electrocardiographic features consistent with the existence of a pro‐arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc‐1β−/− mice had shorter repolarisation intervals. These were likely attributable to altered K+ conductance properties, ultimately resulting in a shortened QTc interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc‐1β−/− systems in widespread cardiac regions.

PGC-1β cooperating with FOXA2 inhibits proliferation and migration of breast cancer cells

“…The peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 (PGC-1) family of transcriptional coactivators, mainly including PGC-1α and PGC-1β, have emerged as being major regulators of mitochondrial biogenesis and cellular metabolism to regulate the cellular bioenergetics [4,5]. The members of PGC-1 family are multifunctional transcriptional co-regulators that take on "molecular switches" in many physiological and pathological processes [6].…”

“…They are highly expressed in oxidative capacity and energy demanding tissues, such as heart, brain, skeletal muscle and brown adipose tissue [7][8][9][10] and considered to be essential for many of exercise response in skeletal muscle [11]. Specifically, PGC-1α and PGC-1β can interact with each other, or interact with multiple transcription factors, such as forkhead/winged helix protein family member FOXO1, and nuclear respiratory factor-1/2 (NRF1/2) in tissue specific manner [5,12] to modulate in mitochondrial biogenesis, fatty acid β-oxidation, adipogenesis, adaptive thermogenesis and tricarboxylic acid cycle [13,14].…”

Cardiomyocyte ionic currents in intact young and aged murine Pgc-1β atrial preparations

“…Recent electrocardiographic studies reported age-dependent slowing of myocardial action potential (AP) conduction in Pgc-1β −/− hearts ( Ahmad et al, 2017 ). Intracellular recording studies then reported age-dependent atrial arrhythmic phenotypes associated with the AP conduction abnormalities in intact Langendorff perfused Pgc-1β −/− hearts ( Valli et al, 2017 ) agreeing with previous reports on their pro-arrhythmic ventricular phenotypes ( Gurung et al, 2011 ).…”

Gene and Protein Expression Profile of Selected Molecular Targets Mediating Electrophysiological Function in Pgc-1α Deficient Murine Atria

“…Thus, although murine hearts show anatomical differences, have higher pacing rates and shorter APs compared to human hearts, they have been established to substantially recapitulate human clinical arrhythmic phenotypes [ 20 , 21 ]. Previous studies have successfully validated both Pgc-1α −/− and Pgc-1β −/− murine models in the study of mitochondrial dysfunction and arrhythmogenesis [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ].…”

“…Furthermore, at a cellular level, extensive loose patch clamp studies implicated reduced Na + currents but unchanged K + currents as a factor for the previously determined slowed conduction velocity in Pgc-1β −/− atria [ 28 ]. At a systems level, electrocardiographic (ECG) studies in these mice have shown irregular PR, PP and RR intervals with differing P wave morphologies as well as reduced atrioventricular node (AVN) function following adrenergic stimulation [ 23 , 24 ]. Interestingly, murine studies of Pgc-1α −/− overexpression have shown changes in Ca 2+ signalling, electrophysiology, and contractile properties [ 25 ].…”