ARTICLE Received 24 Jun 2016 | Accepted 28 Feb 2017 | Published 18 May 2017
DOI: 10.1038/ncomms15097
OPEN
Vagal determinants of exercise capacity Asif Machhada1,2, Stefan Trapp1, Nephtali Marina1, Robert C.M. Stephens3, John Whittle4, Mark F. Lythgoe2, Sergey Kasparov5, Gareth L. Ackland1,6 & Alexander V. Gourine1
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.
1 Centre
for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK. Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London WC1E 6DD, UK. 3 University College London Hospitals NIHR Biomedical Research Centre, London WC1E 6BT, UK. 4 Division of Medicine, University College London, London WC1E 6BT, UK. 5 Department of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK. 6 Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK. Correspondence and requests for materials should be addressed to G.L.A. (email: [email protected]) or to A.V.G. (email: [email protected]). 2 UCL
NATURE COMMUNICATIONS | 8:15097 | DOI: 10.1038/ncomms15097 | www.nature.com/naturecommunications
1
ARTICLE
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15097
E
lite endurance athletes display exceptionally high parasympathetic vagal tone1,2. Although indirect measures of high cardiac parasympathetic activity correlate with enhanced exercise capacity3,4 and lower all-cause mortality5 in athletes and the general population, it remains unclear (and currently contentiously debated6,7) whether vagal tone can be enhanced by exercise training. Alternatively, intrinsically high parasympathetic activity, for example due to genetic factor(s), could predispose some individuals to higher tolerance for
a
1
15 24 h distance (km)
9 7370 8
1
10
200 pA
5
2s
2
2
100 pA 2s
0 0
b
1 2 DVMN firing frequency (Hz)
PRSx8 AlstR eGFP
pTYF
3
(10,372 bp)
IRES2 LVV
eGFP-IR
5 mm
enduring training regimes, essential to achieve superior athletic performance. This study was designed to directly test the hypothesis that the strength of vagal tone determines exercise capacity implying that vagal withdrawal should reduce while vagal recruitment should enhance the ability to exercise. 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). Developmental studies suggested that the DVMN is the primary vagal nucleus and probably the most (evolutionary) ancient central nervous system (CNS) structure which harbours autonomic neurons in vertebrates8,9. Cardiac vagal preganglionic neurons which reside in the DVMN innervate ventricular myocardium10, but have limited control over the chronotropic function9. These neurons are tonically active11 and critically important for metabolic control12. A subset of DVMN neurons provides functional innervation and contributes to the autonomic control of the electrical and contractile properties of the left ventricle (LV) of the heart13,14. In this study, we show that genetic silencing of the DVMN neurons dramatically impairs exercise capacity, while optogenetic recruitment of this neuronal population enhances cardiac contractility and prolongs exercise endurance in rats. These data provide direct experimental evidence that parasympathetic drive generated by the DVMN neurons determines the ability to exercise.
DVMN
Results DVMN neuronal activity and the level of voluntary exercise. First, electrophysiological recordings of DVMN neuronal activity
CC
XII
DVMN 1 mm
c
eGFP (n = 8) AlstR (n =8) 4.0 Work done (kJ)
3.0 2.0 1.0 0 Alst
p=0.03
140
Heart rate (b.p.m.)
MAP (mm Hg)
2.0 1.0
Baseline
eGFP (n = 5) AlstR (n = 7)
150
130 120 110
Pe ak 13,000 12,000 11,000
eGFP (n = 5) AlstR (n = 6) p=0.04
500 450 400 350
se Ba
Time after exercise (s)
+24 h
p=0.03
550
300
30 60 120 180
Alst
600
Pe ak
se
lin e ex Als er t ci se
100
Ba
3.0
+24 h
d
LVdP/dtmax (mm Hg s–1)
p
DOI: 10.1038/ncomms15097
OPEN
Vagal determinants of exercise capacity Asif Machhada1,2, Stefan Trapp1, Nephtali Marina1, Robert C.M. Stephens3, John Whittle4, Mark F. Lythgoe2, Sergey Kasparov5, Gareth L. Ackland1,6 & Alexander V. Gourine1
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.
1 Centre
for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK. Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London WC1E 6DD, UK. 3 University College London Hospitals NIHR Biomedical Research Centre, London WC1E 6BT, UK. 4 Division of Medicine, University College London, London WC1E 6BT, UK. 5 Department of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK. 6 Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK. Correspondence and requests for materials should be addressed to G.L.A. (email: [email protected]) or to A.V.G. (email: [email protected]). 2 UCL
NATURE COMMUNICATIONS | 8:15097 | DOI: 10.1038/ncomms15097 | www.nature.com/naturecommunications
1
ARTICLE
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15097
E
lite endurance athletes display exceptionally high parasympathetic vagal tone1,2. Although indirect measures of high cardiac parasympathetic activity correlate with enhanced exercise capacity3,4 and lower all-cause mortality5 in athletes and the general population, it remains unclear (and currently contentiously debated6,7) whether vagal tone can be enhanced by exercise training. Alternatively, intrinsically high parasympathetic activity, for example due to genetic factor(s), could predispose some individuals to higher tolerance for
a
1
15 24 h distance (km)
9 7370 8
1
10
200 pA
5
2s
2
2
100 pA 2s
0 0
b
1 2 DVMN firing frequency (Hz)
PRSx8 AlstR eGFP
pTYF
3
(10,372 bp)
IRES2 LVV
eGFP-IR
5 mm
enduring training regimes, essential to achieve superior athletic performance. This study was designed to directly test the hypothesis that the strength of vagal tone determines exercise capacity implying that vagal withdrawal should reduce while vagal recruitment should enhance the ability to exercise. 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). Developmental studies suggested that the DVMN is the primary vagal nucleus and probably the most (evolutionary) ancient central nervous system (CNS) structure which harbours autonomic neurons in vertebrates8,9. Cardiac vagal preganglionic neurons which reside in the DVMN innervate ventricular myocardium10, but have limited control over the chronotropic function9. These neurons are tonically active11 and critically important for metabolic control12. A subset of DVMN neurons provides functional innervation and contributes to the autonomic control of the electrical and contractile properties of the left ventricle (LV) of the heart13,14. In this study, we show that genetic silencing of the DVMN neurons dramatically impairs exercise capacity, while optogenetic recruitment of this neuronal population enhances cardiac contractility and prolongs exercise endurance in rats. These data provide direct experimental evidence that parasympathetic drive generated by the DVMN neurons determines the ability to exercise.
DVMN
Results DVMN neuronal activity and the level of voluntary exercise. First, electrophysiological recordings of DVMN neuronal activity
CC
XII
DVMN 1 mm
c
eGFP (n = 8) AlstR (n =8) 4.0 Work done (kJ)
3.0 2.0 1.0 0 Alst
p=0.03
140
Heart rate (b.p.m.)
MAP (mm Hg)
2.0 1.0
Baseline
eGFP (n = 5) AlstR (n = 7)
150
130 120 110
Pe ak 13,000 12,000 11,000
eGFP (n = 5) AlstR (n = 6) p=0.04
500 450 400 350
se Ba
Time after exercise (s)
+24 h
p=0.03
550
300
30 60 120 180
Alst
600
Pe ak
se
lin e ex Als er t ci se
100
Ba
3.0
+24 h
d
LVdP/dtmax (mm Hg s–1)
p
