Karl Popper (7) maintained that the job of the scientist is to erect hypotheses and then attempt to destroy them by testing, and this is what we have been doing. However, the problem is that the concept of high vagal tone in the athlete (and also at night time—another story) and the use of heart rate variability to measure vagal tone have been embedded in the physiologist’s psyche for decades and have gone from hypothesis to fact—something that should not be allowed to happen according to Popper (7). It is therefore not surprising that our ideas are being challenged. However, what is surprising are the reported differences: Billman et al. (1) in the dog report no change in the intrinsic heart rate and an upregulation of HCN4 protein after exercise training, whereas, in the rodent, we report a decrease in the intrinsic heart rate and a downregulation of HCN4 protein (3). We also report a downregulation of HCN4 mRNA, the corresponding funny current, and the role of the funny current in pacemaking in vivo and in vitro, all of which supports a downregulation in HCN4 protein (3). Billman et al. (1) criticize our study saying that rodents are a poor model of the human, mice should be housed at 30°C rather that at 20–22°C, and swimming is a nonphysiological training regimen for mice. However, consistent with our study (3), ample studies of human subjects report a decrease in the intrinsic heart rate after exercise training (2). It has been suggested that mice should be housed at 30°C (6), but this has been subsequently refuted and stated that 20–22°C is the optimal temperature (8). Mice are innate swimmers and training of mice by swimming is a well-established model. It is a validated model and has been shown to mimic human responses to chronic training, e.g., left ventricular hypertrophy and improved skeletal muscle oxidative capacity (4, 5). We have obtained comparable data from rats (trained by treadmill running) as well as mice (trained by swimming) (3). After reading the two opposing viewpoints, it is the job of the readers to make up their minds which to accept. However, more importantly, readers need to carry out experiments of their own to test the conflicting viewpoints, but these experiments must be sufficiently large, well-powered, and quality controlled.
GRANTS
This work was supported by the British Heart Foundation (RG/11/18/29257).
AUTHOR CONTRIBUTIONS
M.R.B. drafted manuscript; M.R.B., Y.W., S.N., J.A., G.H., O.M., and A.D. edited and revised manuscript; M.R.B., Y.W., S.N., J.A., G.H., O.M., and A.D. approved final version of manuscript.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
REFERENCES
- 1.Billman GE, Cagnoli KL, Csepe T, Li N, Wright P, Mohler PJ, Fedorov VV. Exercise training-induced bradycardia: evidence for enhanced parasympathetic regulation without changes in intrinsic sinoatrial node function. J Appl Physiol (1985) 118: 1344–1355, 2015. doi: 10.1152/japplphysiol.01111.2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Boyett MR, D’Souza A, Zhang H, Morris GM, Dobrzynski H, Monfredi O. Viewpoint: is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone? J Appl Physiol (1985) 114: 1351–1355, 2013. doi: 10.1152/japplphysiol.01126.2012. [DOI] [PubMed] [Google Scholar]
- 3.D’Souza A, Bucchi A, Johnsen AB, Logantha SJ, Monfredi O, Yanni J, Prehar S, Hart G, Cartwright E, Wisloff U, Dobryznski H, DiFrancesco D, Morris GM, Boyett MR. Exercise training reduces resting heart rate via downregulation of the funny channel HCN4. Nat Commun 5: 3775, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Evangelista FS, Brum PC, Krieger JE. Duration-controlled swimming exercise training induces cardiac hypertrophy in mice. Braz J Med Biol Res 36: 1751–1759, 2003. doi: 10.1590/S0100-879X2003001200018. [DOI] [PubMed] [Google Scholar]
- 5.Liu W, Zi M, Jin J, Prehar S, Oceandy D, Kimura TE, Lei M, Neyses L, Weston AH, Cartwright EJ, Wang X. Cardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth. Circ Res 104: 905–914, 2009. doi: 10.1161/CIRCRESAHA.108.188292. [DOI] [PubMed] [Google Scholar]
- 6.Maloney SK, Fuller A, Mitchell D, Gordon C, Overton JM. Translating animal model research: does it matter that our rodents are cold? Physiology (Bethesda) 29: 413–420, 2014. [DOI] [PubMed] [Google Scholar]
- 7.Popper K. The Logic of Scientific Discovery. London: Routlidge, 2002. [Google Scholar]
- 8.Speakman JR, Keijer J. Not so hot: Optimal housing temperatures for mice to mimic the thermal environment of humans. Mol Metab 2: 5–9, 2012. doi: 10.1016/j.molmet.2012.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]