Sportology: An Innovative, Interdisciplinary Scientific Wisdom

We proposed a new wisdom called sportology, a scientific approach to the relationship between sports and health. Needless to say, well-trained, non-stressful physical activities are expected to be the most important methods to comprehensively reduce various health problems. While using“sports”and“health”as keywords to deepen the respective specialized sciences involved, sportology simultaneously integrates each of these specializations, creating opportunities where deepening and integration are possible and giving society more effective and efficient academic achievements. In 2007, Juntendo University, with the aid of the Ministry of Education, Culture, Sports, Science, and Technology of Japan, established the Sportology Center, where our motto is to“measure precisely whatever we can measure and make measurable what is not measured in human beings.”Our aim for this center is to translate what we have found at the molecular, cell, and animal levels into demonstrable in human beings. With new findings obtained at this center, we will be able to develop new biomarkers and bioimaging techniques with which we will be able to perform more precise diagnosis and treatment. Among numerous new findings obtained by the Sportology Center, some topics are highlighted.


Introduction
Approximately 50 years ago, I concentrated on identifying the reasons why normoglycemia is maintained during long-term strenuous exercise. By measuring precisely the rate of hepatic glucose production (Ra), rate of muscle glucose utilization (Rd) using a radioisotope tracer dilution technique, and plasma concentrations of insulin and glucagon in dogs, it was clearly demonstrated that exercise induces proportional increases in Ra and Rd, thus maintaining normoglycemia. Ra increases in response to stress-induced glucagon secretion and muscle glucose uptake increases to supply fuel to muscles. At the same time, insulin secretion is suppressed to prevent an excessive Rd in order to avoid hypoglycemia during exercise.
In an animal model of diabetes, depancreatized dogs that received intraportal infusions of insulin and glucagon were forced to run. This experiment also clearly showed that if there is insufficient insulin, hyperglycemia occurred because there was more glucagon action relative to insulin action. On the other hand, if excessive insulin was infused, exaggerated Rd led to hypoglycemia 1) 2) . These data taught me that physical activity prescriptions for patients with diabetes at that time, such as aerobic and resistance exercise, were inadequate, because unusual stressful exercise may cause the secretion of glucagon and catecholamines at the time, which will enhance Ra. Thus, we need to make precise exercise recommendations based on each individualʼs ability to secrete insulin properly and the action of insulin in muscle.
To this day, Japan, Europe, and American Diabetes Associationsʼ guidelines regarding exercise for patients with diabetes have not changed at all 3)-5) . Thus, I was confident that there were no evidencebased individualized recommendations regarding exercise. We had to make the study of sports and physical activity more scientific, which is one of the reasons why we proposed sportology.

Establishment of the Sportology Center, Juntendo University Graduate School of Medicine
We first used the term"sportology"in the preface of the Proceedings of the First International Symposium on Exercise for Diabetes in 1989. We proposed a new field of study called sportology. Sportology is a scientific approach to the relationship between sports and health. Needless to say, well-trained and non-stressful physical activities are expected to be the most important methods to comprehensively reduce various health problems.
While using"sports"and"health"as keywords to deepen the respective specialized sciences involved, sportology simultaneously integrates each of these specialties. This creates opportunities where deepening and integration are possible. It also gives more effective and efficient academic achievements back to society.
In 2007, Juntendo University, with the aid of the Ministry of Education, Culture, Sports, Science, and Technology of Japan, established the Sportology Center. Its motto is to"measure precisely whatever we can measure and make measurable what is not measured in human beings." If examinees come to the center and stay for up to 24 hours, we are able to measure precisely many types of data including minute-by-minute energy expenditure with a human calorimeter chamber system; lipid content in cardiac muscle, liver, pancreas, and thigh muscle; brain structure and function with MRI and MR spectrometry; bone density with dual-energy X-ray absorptiometry (DXA); muscle strength with quantitative isokinetic muscle testing; and insulin-stimulated rates This manuscript was submitted for the Special Issue "Tokyo 2020 Olympic and Paralympic Games, and Sportology", prior to the decision to postpone the Tokyo 2020 Summer Olympics to 2021. Kawamori R: Sportology: an innovative, interdisciplinary scientific wisdom of hepatic glucose output, hepatic glucose uptake, and muscle glucose uptake with the aid of the bedside artificial pancreas that we have developed. We can also perform muscle biopsies to study genomics and epigenetics, proteomics, metabolomics, and other"omics." Periodic measurements reveal the effects of various treatment regimens. We have made possible to precisely measure various indices that are usually not measured in routine medical examinations ( Figure-1). We are sure that our facility is unique in the world. Our aim for this center is to translate what we have found at the molecular, cell, and animal levels into demonstrable in human beings. With the new findings obtained at this center, we will be able to develop new biomarkers and bioimaging techniques with which we will be able to perform more precise diagnosis and treatment.

Establishment of the International Academy of Sportology
Prior to 2011, more than 110 academic medical associations have been established in Japan. However, none of these were based on ideas that originated in Japan. Recognizing the immense potential of sportology, Juntendo University worked hard to build wider interest by organizing the first, second, and third Sportology Precongresses 6) .
In 2011, the creation of the International Academy of Sportology became possible. The Inaugural International Academy of Sportology, led by President Hideoki Ogawa, was held on 5 March 2011 in Tokyo. It concluded with great success. The proceedings of the meeting were published (Figure-2) and sent to 700 association members, universities, and libraries all over the world.
Among special lecturers from various scientific fields invited from all over the world, the lecture by Dr. D.E. Greydanus, a famous pediatrician from Michigan State University, was very stimulating for me. He taught us passionately that all children should participate in healthy sports as early as age 3 for effective neurodevelopment, including brain and motor function, balance, perception, agility, attention, memory, problem solving, analysis, sorting, discrimination, selecting, processing speed, percep-tual ability, motor skills, visual acuity, tracking, breathing, self-awareness, awareness of others, awareness of objects, awareness of others in relation to oneʼs self, control of the extremities, hearing language, comprehension, and thinking ability.
Tragically, within a week of this congress, Japan was hit by a huge earthquake and tsunami. The destruction left people throughout Japan distraught. Sports helped improve the outlook of many people. Sports gave us a sense of hope, such as the victory of Nadeshiko Japan at the 2011 FIFA Womenʼs World Cup.
In recent years, considerable progress has been made in the field of sportology. Thus, we held the Second Congress of the International Academy of Sportology on 12 September 2015 with President Ryuzo Kawamori 7) and the Third Congress of the International Academy of Sportology on 14 October 2017 with President Hiroyuki Daida 8) .

New Findings Obtained from the Sportology Center
Here is a selection of the numerous new findings Juntendo Medical Journal 66 (Suppl 1), 2020

Figure-2 Proceedings of Inaugural International Academy
of Sportology from the Sportology Center. In recent years, the amount of physical activity such as walking time, has been decreasing in Japan across generations.
Our recent data show that decreases in muscle power and muscle volume cause decreased muscle glucose uptake. Spillover of glucose and triglycerides promote lipid accumulation in the liver and adipose tissues, which cause generalized decreases in insulin sensitivity, resulting in glucose intolerance ( Figure-3). Thus, the promotion of increased physical activity in the general population is becoming an urgent issue to be addressed. Insulin resistance is associated with obesity and is known to play an important role in metabolic disorders. However, the exact mechanisms of insulin resistance are not fully understood. We have been measuring ectopic fat using 1 H-MRS for the past 20 years to clarify its role in insulin resistance and metabolic diseases.
The first study we performed was a 2-week interventional study in patients with type 2 diabetes 9) . We recruited 14 patients with type 2 diabetes and divided them into two groups: the diet group (n = 7) and the diet plus exercise group (n = 7). Before and after the intervention, we evaluated ectopic fat in muscle (intramyocellular lipid, IMCL) and liver (intrahepatic lipid, IHL) using 1 H-MRS. We also measured peripheral insulin sensitivity using a hyperinsulinemic-euglycemic clamp. After the 2-week intervention, body fat and body weight decreased by 8.2% and 9.6% in the diet group and 1.5% and 2.3% in the diet plus exercise group. These body fat and body weight changes were trivial, but these interventions had substantial impact on metabolism. For example, fasting glucose levels decreased from 198 to 136 mg/dl in the diet group and from 178 to 133 mg/dl in the diet and exercise group. Circulating triglyceride levels also remarkably decreased from 177 to 120 mg/dl in the diet group and from 216 to 103 mg/dl in the diet and exercise group. Circulating free fatty acids (FFAs) are considered to be a major source of ectopic fat in muscle and liver. However, FFA levels were not altered by the Figure-3 Spillover of glucose and triglycerides promote lipid accumulation in the liver, muscle, and adipose tissues, which cause generalized decreases in insulin sensitivity, resulting in glucose intolerance intervention in either group. These data suggested that weight reduction of only 2% through diet or diet plus exercise remarkably reduces metabolic dysfunction independent of changes in circulating FFA levels. To explore the mechanisms underlying metabolic changes after the intervention, we evaluated ectopic fat in muscle and liver as well as insulin sensitivity. We found that IMCL decreased by 19% and the glucose infusion rate (insulin-stimulated muscle-glucose uptake) increased by 57% in the diet plus exercise group, whereas neither IMCL nor the glucose infusion rate were significantly changed in the diet group. On the other hand, IHL decreased by approximately 30% in both groups.
We also performed dietary interventions in 13 obese subjects without diabetes 10) . Subjects were put on 3 months of calorie restriction to approximately 35 kcal/kg of ideal body weight. With this dietary intervention, 6% weight reduction was observed (from 99.9 ± 7.3 to 93.8 ± 6.6 kg, p < 0.0001). This change was also accompanied by improved glucose tolerance, diastolic blood pressure, glycated hemoglobin levels, and triglyceride levels. In addition, a decrease in IHL (from 12.9 to 8.2%, p < 0.01) and increase in splanchnic glucose uptake (from 13.5 to 35.0%, p < 0.03) were achieved with this intervention. However, the diet program did not affect IMCL concentrations or insulin sensitivity.
Based on these two interventional studies, we believe that diet therapy, i.e., calorie restriction, mainly decreases ectopic fat levels in liver and increased physical activity mainly decreases ectopic fat in muscle. These changes in ectopic fat levels may contribute to improved insulin sensitivity in liver and muscle, which can ameliorate metabolic disorders.
To further understand the role of ectopic fat content and insulin resistance in metabolic diseases, we performed several cross-sectional studies. In most Asians, metabolic abnormalities occur in subjects with normal body mass index (BMI)(< 25 kg/m 2 ) and the pathogenesis of metabolic disease in non-obese subjects is not fully understood. Thus, we recruited non-obese Japanese men who did not have diabetes and evaluated their ectopic fat levels and insulin sensitivity 11) . Among subjects with BMI of 23 to 25 kg/m 2 in this study, impaired insulin sensitivity in muscle, but not in liver, was observed even in those with only one cardiometabolic risk factor. IHL accumulation was associated with impaired insulin sensitivity in both muscle and liver in those subjects. Thus, metabolic disease observed in non-obese Japanese men is closely associated with insulin resistance in muscle and ectopic fat accumulation in liver. Insulin resistance in adipose tissue is one possible mechanism linking insulin resistance in muscle and ectopic fat accumulation in liver. It has been shown that insulin suppress FFA release from adipose tissue; however, in obese subjects, FFAs are readily released from adipose tissue (lipid spillover) due to insulin resistance in adipose tissue. Interestingly, we recently found that some healthy non-obese Japanese men have impaired adipose tissue insulin sensitivity (ATIS) 12) . Subjects with impaired ATIS have moderate lipid accumulation in liver and moderate insulin resistance in muscle. Thus, we hypothesized that FFAs are easily released from adipose tissue in non-obese Japanese men with impaired ATIS and released FFAs may induce insulin resistance in skeletal muscle and lipid accumulation in liver. Thus, muscle insulin resistance and IHL accumulation are simultaneously observed in non-obese men with metabolic disorders.
The studies mentioned above were conducted only in male subjects because in Japan metabolic syndrome develops more readily in men than in women. One reason for the lower prevalence of metabolic disease in Japanese women is that Japanese women have lower BMI than Japanese men. Japan has the second highest prevalence of underweight women among developed countries, similar to the prevalence of underweight among women in developing countries.
Some studies showed that underweight and overweight are both associated with a higher incidence of diabetes in the Japanese population. However, the mechanisms leading to impaired glucose metabolism in underweight Japanese women are not fully understood. Thus, we recruited 30 underweight postmenopausal women. We found that 37% (11/30) were diagnosed as having impaired glucose tolerance 13) . In postmenopausal underweight women, 2-hour glucose levels during OGTT are negatively correlated with lean body mass (r =-0.55, p < 0.01) and insulinogenic index (r =-0.42, p = 0.02) and positively correlated with IMCL levels (r = 0.40, p = 0.03). These data suggest that impaired insulin secretion as well as decreased muscle mass and ectopic fat accumulation in muscle may be important in the pathogenesis of impaired glucose metabolism in underweight women.
Based on these studies, we should consider the role of sports in health maintenance. It is well known that aerobic exercise reduces muscle insulin resistance and metabolic disease. However, aerobic exercise does not substantially increase muscle mass, while resistance exercise does. Therefore, it would be reasonable to individualize physical activity depending on the amount of skeletal muscle mass and degree of muscle insulin sensitivity. Further study is clearly required for this individualization. The Bunkyo Health Study 14) will provide more data for this purpose.
Shimada, Daida, and others in the Department of Cardiovascular Medicine in the Juntendo University Graduate School of Medicine are interested in myocardial triglyceride (TG) accumulation. Myocardial TG content is found in ectopic fat in myocardium, which is associated with various metabolic disorders and cardiovascular diseases. Elevated myocardial TG levels have been reported to trigger pathological changes, including apoptosis, left ventricular (LV) contractile dysfunction, LV diastolic dysfunction, and LV remodeling.
They succeeded in developing a 1 H-MRS method to measure myocardial TG content. First, they evaluated myocardial TG content in 37 apparently healthy Japanese subjects without heart disease. The mean myocardial TG level was 0.85 ± 0.40%. Myocardial TG levels were significantly associated with percent body fat, serum triglyceride levels, estimated glomerular filtration rate, anaerobic threshold, maximal load during cardiopulmonary exercise testing, LV end-diastolic volume, and LV end-systolic volume. They found that 1 H-MRS may be useful for noninvasive assessment of the associations between myocardial TG levels and various clinical parameters, including those reflecting obesity, metabolic disorders, cardiac morphology, and exercise capacity, in Japanese subjects 15) .
Next, they examined myocardial TG levels in 10 male endurance athletes and 15 healthy male controls. There were no significant differences in clinical characteristics including age, anthropometric parameters, blood test results, or arterial stiffness between the two groups. Peak oxygen uptake, LV end-diastolic volume, LV end-systolic volume, LV mass, peak ejection rate, and peak filling rate were significantly higher in the athlete group than in the control group. Myocardial TG levels were significantly lower in the athlete group (0.60 ± 0.20%) than in the control group (0.89 ± 0.41%) (Figure-4). Myocardial TG levels were negatively correlated with LV end-diastolic volume, LV end-systolic volume, LV mass, and epicardial fat volume. Lower levels of myocardial TG content were observed in endurance athletes and were associated with morphological changes related to physiological LV alterations in athletes, suggesting that metabolic imaging to measure myocardial TG content with 1 H-MRS may be a useful technique for noninvasive assessment of the"athleteʼs heart" 16) .
Turning to patients with left ventricular hypertrophy (LVH) and pathological LV alterations, they examined whether myocardial TG levels in patients with hypertrophic cardiomyopathy (HCM) and hypertensive heart disease. Myocardial TG levels were significantly higher in the HHD group (2.14 ± 1.29%) than in the HCM group (1.09 ± 0.72%). Myocardial TG levels were significantly and negatively correlated with LV mass and stroke volume in the HCM and HHD groups, respectively. Myocardial metabolism may differ between patients with HCM and HHD. Measurement of myocardial TG levels using 1 H-MRS may be useful for evaluating the myocardial metabolic features of LVH 17) .
Ishijima, Okada, Kaneko, and others from the Department of Medicine for Orthopaedics and Motor Organ and the Department of Pathophysiology for Locomotive and Neoplastic Diseases in the Juntendo University Graduate School of Medicine have been trying to prevent locomotive syndrome. Locomotive syndrome is defined as a condition associated with restriction in oneʼs ability to walk or lead a normal life due to dysfunction in one or more of the parts of the locomotive system, including the muscles, bones, joints, cartilage or intervertebral discs. This syndrome especially refers to a need for nursing care because of problems with the locomotive organs or such a need in the near future. Recent epidemiological studies have revealed that the onefourth of elderly individuals who require special assistance or nursing care have locomotive disorders Kawamori R: Sportology: an innovative, interdisciplinary scientific wisdom in Japan.
Osteoarthritis of the knee (knee OA), osteoporosis, and spinal canal stenosis due to spondylosis are three major locomotive disorders that cause elderly individuals to require special assistance or nursing care. Using the concept of sportology to prevent locomotive syndrome with support from the Juntendo Sportology Center, they have been focused on the effects of knee OA on the lives of elderly individuals and the pathophysiology and management of this disease. These investigators believe that their project could contribute directly the concepts of locomotive syndrome and sportology.
Knee OA is an increasingly important public health concern because its prevalence is increasing with societal aging. However, no disease-modifying treatments for knee OA currently exist; all currently available treatments modify symptoms. Pain is the most prominent and disabling symptom of OA. It is also one of the factors predicting the progression of OA. There is an urgent need to improve the understanding of the pathophysiology and symptomology of this disease. The role of synovitis in OA has recently attracted particular attention. Synovitis is a potential indicator of knee pain and a predictive factor for both structural and symptomatic progression of the disease. They have revealed that pain is associated with synovitis from early-stage to end-stage knee OA. However, the pathophysiology associated with pain varies by knee OA severity 18) 19) . Knee OA is anticipated to become more influential in our society in the future. Currently, surgical treatment such as joint replacement surgery or osteotomy is not indicated for patients who have radiographic end-stage knee OA but no pain. Although all surgical treatments are associated with a risk of side effects during and after the operation, symptoms, especially mobility impairment, should also be considered in addition to pain when determining the indications for surgery to treat knee OA, because locomotive function or mobility is critical to maintaining health in the elderly. They have examined preoperative factors related to indications for surgery and postoperative ability to perform activity of daily living (ADLs) in patients with knee OA. They are also continuing to focus on how to prevent disease progression.
In addition, since OA is a lifestyle-related disease, they should also take measures to manage pre-clinical, middle-aged, asymptomatic subjects with knee OA. Moreover, knee OA may also affect other organs, such as the heart. They are trying to disseminate the current understanding of asymptomatic vary early-stage to end-stage OA and establish novel prevention and treatment methods according to the pathophysiology of these diseases based on the concepts of locomotive syndrome and sportology. They are focusing on the pathophysiology of early-stage knee OA in both basic 20) and clinical 21) 22) research settings (Figure-5) 22) . Furthermore, they are currently planning to examine the association between changes in knees with OA and metabolic and cognitive function of elderly individuals in the Bunkyo Health Study cohorts 14) .

Pending Issues in Sportology
There are still a lot of pending issues in the field of sportology, such as childhood sports and problems related to overuse injuries. Recently, with advances in brain imaging techniques, the neurocognitive impact of sports-related concussions in adolescents has been revealed. We are now actively trying to identify damage from concussions in terms of tau accumulation in the brain. How to prevent concussions is also an urgent theme for sportology.
There are many top-class women athletes with amenorrhea who visit the Sportology Center. It is very difficult to cure them. We have to investigate knee with OA that has osteophytes and medial meniscus extrusion (MME) A: Normal knee. The medial meniscus is tightly fixed to the coronary ligament in the medial tibial plateau. B: Relationship between MME and medial tibial osteophyte length based on conventional MRI visualization. Note that MME length appears greater than osteophyte length. C: Relationship between MME and medial tibial osteophyte length based on T2 mapping MRI. Note that the edge of the extruded medial meniscus matches the cartilaginous part of the osteophyte. Bp, bony part of the osteophyte; Cp, cartilaginous part of the osteophyte; M, medial meniscus.
how much exercise is allowed in each individual to prevent such risks. To me, the most important pending issues involve "brains and brawn."Do brains and brawn help each other? Or is it pulling of the foot? With advances in the understanding of brain function in human beings, several minute changes in the brain in response to various strength exercises have been revealed. The most suitable method to activate brain function in each subject will be established soon.
The journal Nature was interested in sportology. We have answered many questions from them. They were very kind to publish a special article entitled"Sportology-an emerging field"(Nature 549: 7670, 2017). In this special feature, among the various themes in sportology, they were most interested in the investigation of reasons why we are so excited with just watching and cheering during games lively.
We are now working hard to combine with various fields of medicine to identify the reasons why many people watch sports and are excited and delighted. Does watching sports enhance brain function? If so, is this effect different from when hearing splendid music?
To get fruitful outcomes from sportology, more different fields in science should work together. I am confident that sports have a strong power. We have to understand the reasons why.

Future of the Sportology Center
With this background, to advocate an unprecedented concept of disease prevention, Juntendo University is engaged in an interdisciplinary university-wide research initiative called"Health Creation by Sports Science that is Based on Metabolic Research."This project will focus on metabolic functions, especially those of mitochondria that produce energy for cells, by fusing research on the genomics of mitochondrial diseases with research on the acquisition of supernormalness and disease prevention. This project will further explore genetic backgrounds, biomarkers, and training methods that will contribute to health creation, with close collaboration among the Institute for Health and Medical Sports, Sportology Center, Intractable Disease Research Center, and Faculty of International Liberal Arts. This could only be done at Juntendo University where unique research on both athletes and patients are conducted.
Sports is old, gold, retold ! However, sportology is still brand-new. Sportology has been asked to prove its real worth urgently. Thus, please couple your scientific specialty to other specialties under the banner of sportology. I am sure that the Sportology Center is where prevention of disease begins. Letʼs make sportology a kind of disruption that drives disease prevention !