Vagal determinants of exercise capacity

Asif Machhada,Robert C.M Stephens,Sergey Kasparov,Alexander V Gourine,Nephtali Marina,Gareth L Ackland,Mark F Lythgoe,John Whittle,Stefan Trapp

doi:10.1038/ncomms15097

Abstract

Indirect measures of cardiac vagal activity are strongly associated with exercise capacity, yet a causal relationship has not been established. Here we show that in rats, genetic silencing of the largest population of brainstem vagal preganglionic neurons residing in the brainstem’s dorsal vagal motor nucleus dramatically impairs exercise capacity, while optogenetic recruitment of the same neuronal population enhances cardiac contractility and prolongs exercise endurance. These data provide direct experimental evidence that parasympathetic vagal drive generated by a defined CNS circuit determines the ability to exercise. Decreased activity and/or gradual loss of the identified neuronal cell group provides a neurophysiological basis for the progressive decline of exercise capacity with aging and in diverse disease states.

Highlights

Indirect measures of cardiac vagal activity are strongly associated with exercise capacity, yet a causal relationship has not been established
Indirect measures of high cardiac parasympathetic activity correlate with enhanced exercise capacity[3,4] and lower all-cause mortality[5] in athletes and the general population, it remains unclear whether vagal tone can be enhanced by exercise training
We tested it in rodents by genetically targeting the key population of vagal preganglionic neurons that reside in the brainstem’s dorsal vagal motor nucleus (DVMN)

Summary

Results

DVMN neuronal activity and the level of voluntary exercise. First, electrophysiological recordings of DVMN neuronal activity c. One hundred fifteen DVMN neurons recorded in vitro (that is, in the absence of afferent modulation from the periphery and the rest of the CNS) from 14 mice exhibited a mean spontaneous firing rate of 1.46±0.12 Hz. The mean DVMN neuronal action potential firing rate (determined for each mouse; 8 cells on average) in the range 0–1.7 Hz increased with the amount of voluntary exercise performed by the animals in a 24 h period (Fig. 1a), supporting the hypothesis that intrinsic vagal activity may determine the ability to exercise. The mean DVMN neuronal action potential firing rate (determined for each mouse; 8 cells on average) in the range 0–1.7 Hz increased with the amount of voluntary exercise performed by the animals in a 24 h period (Fig. 1a), supporting the hypothesis that intrinsic vagal activity may determine the ability to exercise This largely linear relationship did not continue with spontaneous mean firing rates of DVMN neurons above 2 Hz (recorded in brainstem slices of two animals; Fig. 1a).

50 Baseline Dobutamine Baseline Dobutamine Baseline Dobutamine f

Discussion

Methods