Graphical Review
Experiments of nature and within species comparative physiology

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Highlights

  • Unique groups of patients can be studied to better understand fundamental problems in physiology.

  • There are several nuances regulating circulatory responses to exercise including the CNS.

  • Non-linear increases in ventilation during heavy exercise are not tied to rises in lactate in patients with McArdle's Disease.

  • Left-shifts in the oxygen dissociation curve appear to be protective for humans exercising in hypoxia.

Abstract

This graphical review highlights a focused application of a key principle (‘Krogh Principle’) identified by Nobel-prize winning physiologist Professor August Krogh (1874–1949) that states “for many problems there is an animal on which it can be most conveniently studied”. We apply the Krogh Principle to human physiology by proposing that “for many problems there is a unique group of humans on which it can be most conveniently studied”. As such, we present 5 unique human case studies. Case 1 discusses whether signals from exercising muscles cause blood pressure to rise using a patient with a spinal cord lesion. Case 2 investigates the role of the sympathetic nervous system in the blood pressure response to exercise using patients who have undergone sympathectomy for hypertension. Case 3 asks whether increases in blood lactate are necessary for the non-linear increase in breathing with heavy exercise using patients with McArdle's disease. Case 4 applies fundamental scaling principles from comparative physiology to elite athletes to investigate the role of body size on maximal aerobic capacity. Finally, Case 5 describes our recent work that investigates whether a left shift in the oxygen hemoglobin dissociation curve can facilitate hypoxic exercise using patients with left-shifted hemoglobinopathies. In summary, we have expanded the inter-species message of the August Krogh Principle and highlighted the need to search for odd examples and experiments of nature. In this context, observations from unusual humans are a source of insights into physiology, which may be translated into therapeutic approaches for disease.

Introduction

Although often recognized for his Nobel-Prize winning discoveries in cardiovascular and respiratory physiology, Professor August Krogh was also a pioneer of comparative physiology. In fact, his dissertation focused on the gas exchange mechanisms of the skin and lungs of frogs. Thus, Hans Krebs dubbed, the ‘Krogh principle’ — “for many problems there is an animal on which it can be most conveniently studied” — has become a cornerstone of comparative physiology (Green et al., 2018; Krebs, 1975). This graphical review highlights a focused adaptation of the Krogh Principle to human physiology by proposing that “for many problems there is a unique group of humans on which it can be most conveniently studied”. Using this focused application of the Krogh principle, we describe the use of human “experiments of nature” – studies on rare groups of humans including patients with unusual conditions – to address five key questions in physiological research. Because the physiological response to exercise was a central interest of both Krogh and his colleagues and our laboratory, this perspective focuses on the control of respiration, circulation, and gas exchange in exercising humans. To achieve this objective we will present five human physiological case studies in chronological order.

Section snippets

Background

As the physiological responses to exercise began to be systematically studied in the late 1800's, it was noted that both heart rate and ventilation increased in moments preceding the onset of exercise and the degree of these increases seemed to be associated with exercise intensity. Shortly thereafter, investigators like Krogh, his colleagues, and their contemporaries began to study the origin of the intrinsic factor(s) that govern the rise in blood pressure during exercise — The brain? The

Background

There are redundant mechanisms that contribute to a rise in blood pressure during exercise. This rise in blood pressure occurs despite the release of multiple vasodilatory substances from the active muscles, which augment blood flow to supply active muscle with oxygen and remove CO2 and other by-products of contraction (Marshall et al., 1961).

Dogma

The factors that cause peripheral vasodilation during skeletal muscle contraction may attenuate or eliminate the ability of the sympathetic nervous system

Background

When humans exercise, ventilation and gas exchange rise to meet the metabolic demands of the active muscles. In most circumstances, during activities like walking, running, or cycling there is a linear relationship between metabolic rate and minute ventilation. However, during heavy exercise there is a non-linear rise in minute ventilation, which is temporally associated with a rise in blood lactic acid concentrations. Depending on an individual's aerobic fitness, this non-linear rise in

Background

Allometric scaling of physiological responses to body size is a fundamental principle in comparative physiology, typically used in “mouse to elephant” comparisons over several orders of magnitude of body size (Brody and Lardy, 1946; Lindstedt, 2020; Rubner, 1883). The importance of body mass as a determinant of metabolic rate has been a key area of focus for this work.

Dogma

Despite spanning broad magnitudes of size, animals obey simple scaling laws which relate to how biological features change with

Background

The oxygen hemoglobin dissociation curve can be shifted by internal and external factors to bind oxygen more or less tightly. CO2, pH, 2–3 bisphosphoglyceric acid (BPG) and temperature are key factors that influence the binding affinity of oxygen to hemoglobin.

Dogma

During hypoxia, a right shift in the oxygen hemoglobin dissociation curve (i.e., lesser oxygen affinity) is thought to be beneficial to enable more oxygen to be released at the tissues to protect against tissue hypoxia.

The experiment of nature

Many species

Summary

This graphical review highlights a focused application of the ‘Krogh Principle’ and describes the use of human “experiments of nature” to address five key questions in physiological research. In this brief paper we have adapted the inter-species message of the August Krogh Principle and highlighted the ongoing and general need to search for rare examples and experiments of nature. This search also points to the continuing power of small data. In this context, observations from unusual humans

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Acknowledgements

MJJ was supported by the National Institutes of Health (R-35-HL139854) and the Mayo Foundation for Medical Education and Research. JWS was supported by the National Institutes of Health (1-F32-HL154320-01), SAK was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) post-doctoral fellowship (PDF-532926-2019).

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