Exercise physiology and physical inactivity
Exercise physiology studies how the body responds and adapts to physical activity and to inactivity, and it uses the stress of exercise as an experimental model. That model showed that exercise promotes glucose uptake independently of insulin and how it changes gene expression, and it will be needed to understand better how physical inactivity contributes to the chronic diseases it has been linked to, a link that rested in 2012 mainly on association.
Exercise as an experimental model
Exercise physiology is the sub-discipline that studies the functional responses and adaptations associated with physical activity or inactivity. Its main focus has been to understand the responses and adaptations to exercise in healthy people and in those with chronic diseases.
Exercise physiology has not always been held in the same regard as other sciences. In some eyes exercise is merely taking part in sport, which needs little experimentation, objectivity or creation of knowledge, and for others it is something people should do but a relatively insignificant contributor to understanding chronic disease. For a small but dedicated group of physiologists, however, exercise is one of the most fascinating and powerful experimental models. Despite the view that it is confined to the study of sport, exercise physiology has contributed to some of the most important scientific advances, particularly in understanding metabolic function. So its contribution to scientific knowledge should not be underestimated.
Physiology is an integrated science that advances understanding of the function of the human body, and it underpins medicine and disease prevention as well as more specific disciplines such as molecular biology, immunology and environmental biology. Because physiology is often best studied under extreme conditions, exercise provides an excellent experimental model for answering important scientific questions. The physiological stress of exercise is a unique model for understanding the regulation of energy expenditure, gene expression and glucose utilisation. It is also a unique model for investigating normal body function and the factors that contribute to the development and progression of chronic disease.
One of the best and earliest examples is A. V. Hill's research on heat production in muscle, for which he received the Nobel Prize in 1922. He measured the total work performed during exercise and the energy expended to perform it, and established that the human body is not very efficient at converting stored energy into mechanical energy and instead produces heat that has to be dissipated. That result is still relevant and has formed the basis of much of what exercise physiology textbooks teach. Exercise has been used to answer some of the most basic research questions about heat production and the role of muscle as an endocrine organ, and to help treat patients with chronic disease.
Insulin-independent glucose uptake during exercise
The dramatic increase in the prevalence of type 2 diabetes has focused research on understanding glucose uptake. Under normal circumstances, ingested glucose stimulates the release of insulin. When insulin binds its receptors, mainly on muscle, liver and fat cells, a series of intracellular events translocates glucose transport proteins to the cell surface, and glucose is taken up. People who gain weight or develop type 2 diabetes become resistant to the action of insulin. Fewer transport proteins are then inserted into the cell membrane, and compensatory actions such as increased insulin production maintain glucose homeostasis. By 2012 a concerted effort to characterise the insulin signalling cascade had produced thousands of papers over two decades, and the pathway was still not fully characterised.
Insulin is the most important hormone for lowering blood glucose, but exercise has been known for some time to lower blood glucose too, in healthy people and in those with abnormal glucose tolerance. When the insulin signalling cascade was studied during exercise it was not activated, yet the glucose transporters were translocated, so exercise facilitates glucose disposal independently of insulin. That finding gives a scientific basis for exercise in the treatment of type 2 diabetes, and a model for identifying new drug targets. The main pathways that promote glucose uptake during exercise are the stress-responsive cascades AMPK and p38 MAPK and the calcium signalling that arises from muscle contraction. In 2012 their significance, and their potential as glucose-lowering targets that do not act through insulin, were still being explored.
Exercise and gene expression
The genomic era promised gene targets that would explain human health and disease. The technology that made genomic techniques accessible and affordable was a benefit, but it also shaped the questions asked. Much emphasis fell on the effect of individual genes on whole-body and tissue-specific responses, which cannot be studied in humans except in rare monogenic diseases, so research shifted towards animal and cell-based models. The impact of exercise physiology was blunted during that period, but the post-genomic era has greater potential for it. The proportion of human disease with genetic causes, even polygenic ones, might be smaller than first anticipated, while the interaction between environmental factors and the epigenome may play a major role.
Epigenetic modification has emerged as a key regulator of gene expression. The DNA sequence stays unchanged, but some of its nucleotides are methylated, which alters how efficiently a gene is transcribed. The epigenetic signature is heritable, and much of the research has asked whether traits of chronic disease pass from parent or grandparent to offspring this way. DNA methylation can also be modified by exercise. In healthy but inactive people, whole-genome methylation decreased after an acute bout of exercise. The hypomethylation of the promoter regions of key metabolic genes, and the expression of their mRNA that followed, depended on the intensity of the exercise. These changes were evident 3 hours after exercise but were not observed after a period of exercise training, which suggests that exercise regulates the epigenetic profile and gene expression acutely. In 2012 the time course of the changes, and whether exercise can modulate the heritability of epigenetic modification, still needed research.
The argument that exercise regulates gene expression is quite strong. The human genome evolved to support physical activity, in particular hunting and gathering food, and ancestors who could not hunt and gather effectively would not have survived. So the gene expression profile, and the metabolic gene profile in particular, reflects the demand for energy production and the amount of physical activity. The number and size of mitochondria, the aerobic powerhouse of cells, are a clear example. People who exercise regularly have more mitochondria than inactive, obese or type 2 diabetic people. Exercise is quite a potent stimulator of metabolic gene expression: it can significantly increase the expression of many mitochondrial proteins in 7–14 days and lead to mitochondrial biogenesis in just a few weeks. But the amount of mitochondria is malleable, and a sustained period of inactivity requires less energy production and so reduces the energy-producing machinery of the mitochondria.
Exercise has also helped elucidate how transcription factor complexes are regulated. Peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) is a transcriptional co-activator proposed as a coordinator of metabolic gene expression. Exercise increases its expression in skeletal muscle, and it has been implicated in many of the adaptations to exercise, including mitochondrial biogenesis, angiogenesis, muscle fibre composition and glucose transport. The same intracellular proteins that exercise activates to facilitate glucose transport are translocated to the nucleus and mediate PGC-1α transcription. This work identified irisin, an exercise-activated, PGC-1α-dependent protein released into the circulation. Irisin is a chemical messenger with endocrine action on adipose tissue, and it promotes the conversion of white adipose tissue to the more bioenergetic brown form. Over-expressing the gene encoding irisin improved glucose homeostasis and obesity in high-fat-fed mice, and irisin was required for many of the effects of exercise on gene expression in adipose tissue. Exercise is thus an excellent model for understanding the regulation of gene expression and for identifying myokines, chemical messengers that skeletal muscle releases to communicate with other tissues and regulate physiological processes in an endocrine fashion.
Energy balance, inactivity and calorie restriction
Hunting and gathering food required a large energy expenditure until recently. Technology has since sharply reduced the energy needed to obtain food, and it has reduced occupational and recreational energy expenditure, while energy intake has risen through energy-dense industrialised products. The net outcome is a positive energy balance: energy is stored, which increases fat mass and ectopic fat and leads to the risk factors of the metabolic syndrome, type 2 diabetes and cardiovascular disease. In tackling obesity-related disease most emphasis has been placed on dietary modification, but the contribution of physical inactivity appears to have been underestimated.
Continuing to recommend calorie restriction is not feasible, because people on it cannot consume enough of the vitamins and minerals required to maintain normal function. Physical activity needs to increase instead, allowing a nutrient intake that matches expenditure and contributes to health.
Inactivity as an active process
Physical inactivity can induce separate physiological processes that actively promote, among other things, muscle atrophy and insulin resistance. Findings by 2012 to that effect challenged the long-held assumption that the benefits of regular exercise are simply lost when training stops. In 2012 this paradigm shift was very likely to change how activity, and more importantly inactivity, are viewed.
Inactivity and cognitive decline
Physical inactivity is most often associated with metabolic disease, but by 2012 evidence was increasing for a role in other chronic conditions. Its link with the age-related decline in cognitive function was already attracting attention. People who are less active or have low fitness tend to be at greater risk of incident dementia and Alzheimer's disease. The number of older people is increasing, and people with cognitive impairment need more support, supervision and clinical management, which has serious implications for the cost of healthcare systems. It has been speculated that the increased risk may be associated with decreased blood flow to the brain, atrophy of parts of the brain or reduced neural plasticity, but in 2012 the evidence was not robust enough for conclusive statements.
The evidence linking inactivity to chronic disease
Despite increasing emphasis on the need for exercise, the extent of its importance for maintaining good health appeared in 2012 to have been underestimated, and the underlying mechanisms were still not clearly understood. Physical inactivity had been linked to more than 30 chronic diseases, but mainly by association studies. The next phase of research needed more direct evidence of cause and effect, from mechanistic studies and randomised controlled trials. Inactivity research had reached the phase in which its relationship to the causes of chronic disease needed to be investigated in clinical trials, and those trials bring that research to medical writers. Exercise physiology will be needed to understand better how physical inactivity contributes to the development of chronic diseases. In 2012 the physiology of exercise and inactivity was expected to have the potential to make a major impact on the understanding of chronic diseases in the following decade.