Changes in Heart Rate and Its Regulation by the Autonomic Nervous System Do Not Differ Between Forced and Voluntary Exercise in Mice.

Robert Lakin,Farzad Izaddoustdar,Nazari Polidovitch,Jack M Goodman,Peter H Backx,Camilo Guzman

doi:10.3389/fphys.2018.00841

Abstract

Most exercise studies in mice have relied on forced training which can introduce psychological stress. Consequently, the utility of mouse models for understanding exercise-mediated effects in humans, particularly autonomic nervous system (ANS) remodeling, have been challenged. We compared the effects of voluntary free-wheel running vs. non-voluntary swimming on heart function in mice with a focus on the regulation of heart rate (HR) by the ANS. Under conditions where the total excess O2 consumption associated with exercise was comparable, the two exercise models led to similar improvements in ventricular function as well as comparable reductions in HR and its control by parasympathetic nervous activity (PNA) and sympathetic nervous activity (SNA), compared to sedentary mice. Both exercise models also increased HR variability (HRV) by similar amounts, independent of HR reductions. In all mice, HRV depended primarily on PNA, with SNA weakly affecting HRV at low frequencies. The differences in both HR and HRV between exercised vs. sedentary mice were eliminated by autonomic blockade, consistent with the similar intrinsic beating rates observed in atria isolated from exercised vs. sedentary mice. In conclusion, both forced and voluntary exercise induce comparable ventricular physiological remodeling as well as HR reductions and HR-independent enhancements of HRV which were both primarily dependent on increased PNA.New and noteworthy–No previous mouse studies have compared the effects of forced and voluntary exercise on the heart function and its modulation by the autonomic nervous system (ANS).–Both voluntary free-wheel running and forced swimming induced similar improvements in ventricular contractile function, reductions in heart rate (HR) and enhancements of HR variability (HRV).–HR regulation in exercised mice was linked to increased parasympathetic nerve activity and reduced sympathetic nerve activity.– HRV was independent of HR and depended primarily on PNA in both exercised and sedentary mice.– Complete cardiac autonomic blockade eliminated differences in both HR and HRV between exercised and sedentary mice.

Highlights

Studies in mice have been largely limited to forced exercise models, which have been linked to psychological stress (Dishman et al, 2006; Morgan et al, 2015), anti-depressant behavior (Slattery and Cryan, 2012), and elevated corticosterone levels (Gong et al, 2015), though these findings are not universal (Aschar-Sobbi et al, 2015)
To assess the role of parasympathetic and sympathetic nervous systems in HR Variability (HRV), mice were treated with atropine (2 mgkg−1) and propranolol (10 mgkg−1), respectively, which resulted in complete cardiac autonomic blockade, as we have shown previously (Aschar-Sobbi et al, 2015)
VO2 were measured during exercise in order to assess the levels of effort and work performed associated with exercise over the 6-week training period

Summary

Introduction

Studies in mice have been largely limited to forced exercise models, which have been linked to psychological stress (Dishman et al, 2006; Morgan et al, 2015), anti-depressant behavior (Slattery and Cryan, 2012), and elevated corticosterone levels (Gong et al, 2015), though these findings are not universal (Aschar-Sobbi et al, 2015). Mice normally display high sympathetic nerve activity (SNA) combined with low parasympathetic nerve activity (PNA) at baseline compared to humans (1996, Gehrmann et al, 2000), suggesting that mice are generally unsuitable for assessing the changes in HR and its regulation by the ANS induced by exercise (Billman et al, 2015). The origins of HR control and its modulation by exercise are especially relevant because HRV is used to non-invasively assess cardiac autonomic nervous function in the context of heart disease and its treatment by interventions such as exercise (Kishi, 2012; Florea and Cohn, 2014) For these purposes, HRV is dissected typically into rapid “high frequency” (HF) components associated with breathing and PNA as well as slower “low frequency” (LF) components to assess SNA (1996), this appears to depend on species and experimental conditions (Pomeranz et al, 1985; Pagani et al, 1986)

Methods

Results

Conclusion