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Pushing Back the Frontiers of Sports Science with State-of-the-Art Technologies in Molecular and Cellular Biology

Takayuki Akimoto
Professor, Faculty of Sport Sciences, Waseda University

Interest in the health benefits of exercise

How to lead a long, healthy life is a common concern in Japan’s super-aged society. Unfortunately, research on healthy living is not as advanced as that conducted for treatment of diseases. The health benefits of exercise are considered obvious, but their molecular mechanisms are little understood at present. Exercise triggers many reactions in our bodies. The body temperature rises, and the heartbeat and breathing speed up. Muscles experience the input of dynamic stimuli (i.e., mechanical stress), which is one of the focuses of the research carried out at my laboratory. We are exploring how muscles adapt to the mechanical environment at the cellular and molecular levels.

Having played rugby at high school, university and graduate school, I have always been interested in research related to exercise and health. The secret to leading healthy lives has been ascertained through epidemiological studies. These involve periodically collecting data from a large cohort regarding lifestyle, exercise experience, health conditions and so forth. Then, the data is analyzed statistically to identify correlations, such as the benefits of exercise on health, and the relationship between dietary habits and health. One well-known example of these studies is the Framingham Heart Study, which started in the 1940s in the United States, and a variety of systematic surveys have been carried out since. Waseda University has also launched an epidemiological study known as the WASEDA's Health Study project, targeting alumni.

Epidemiological studies help us discover more about our health. Nevertheless, for its scientific understanding, it is important to clarify what is actually happening in our bodies, for instance, the mechanism behind how exercise affects our bodies and brings about a state of health. This is where my main interest lies. Aiming to reveal the relationships between exercise and health, we make use of methods in molecular biology and genetics to study the functions of muscles at the molecular and cellular levels.

I was engaged in research on autoimmune diseases as a Ph.D. candidate , but switched to my current field of research when I started working as a research associate at The University of Tokyo. When I began cell culture experiments, the first question was how to apply mechanical stress to the cells. It was no surprise that very few researchers in the world had worked on this. Usually, cell culture experiments are conducted by placing cells on plastic petri dishes. After trial and error, we adopted a method of attaching cells to a silicon membrane and applying mechanical stress to them by stretching this base membrane. According to my initial hypothesis, such stretching would stimulate the kind of development and differentiation of cells to help the bulking up of muscles. Yet, our findings were the total opposite, and the differentiation was inhibited instead. The cause is still unknown, however, I believe cells have a tendency to retain their undifferentiated state under mechanical stress.

Visiting a state-of-the-art research center in the United States

Among the several types of muscles, we are mainly focusing on skeletal muscle. It is highly plastic tissue that accounts for roughly 40 percent of the body, the largest portion by weight. Skeletal muscle is strengthened by exercise or weakened by aging and/or lack of exercise, meaning that its condition depends on the environment. The obvious role of skeletal muscle is to move our bodies, which is vital for our survival, such as when escaping from danger or gathering food. We should also remember that skeletal muscle stores and generates energy for moving and maintaining our body temperature. Skeletal muscle is composed of fast and slow fibers, both of which are distributed throughout our bodies. They have different contraction speeds and metabolic characteristics.

Fast muscle fibers mainly generate energy by breaking down glucose (sugar), whereas slow fibers are fueled by burning sugars and fatty acids using oxygen. This makes slow fibers far more energy efficient. This energy metabolism is mainly used during aerobic exercise. Today, among lifestyle-related diseases raising social concern, metabolic disorders are on the rise, including metabolic syndrome and diabetes. Increasing the amount of slow muscle is expected to have a positive effect on these metabolic diseases by enhancing energy efficiency.

Figure 1 Mechanism of transcriptional activation of PGC-1α involved in exercise (Source: Akimoto et al. 2005)

In my third year as a faculty member, I had an opportunity to work at Duke University as a visiting researcher. I was assigned to a laboratory led by one of the leading scientists on skeletal muscle plasticity. While studying everything from the basic methodologies to the cutting-edge technologies of molecular biology, I began to conduct my own research. Based on the research theme of the adaptation mechanism of skeletal muscle to mechanical stress, we prepared genetically modified mice, and evaluated and analyzed their individual muscle phenotypes. We also conducted experiments with cells to study their adaptation mechanism in greater detail. As a result, our research clarified that intracellular signaling (p38 MAPK) derived from mechanical stress and/or muscle contraction plays an important role in slow muscle specialization through transcriptional activation of transcriptional co-activator PGC-1α. This paper attracted international attention, and we were even awarded a prize from the American Physiological Society.

The desire to nurture researchers

At the laboratory during my years at Duke University

My stay at Duke was supposed to last for only a year. However, I ended up leaving my university in Japan and remained at Duke University for an additional one and a half years as a researcher. Duke University is famous for its prestigious graduate school in business, and while I was in the U.S., I played rugby on the team affiliated with the school. Then, our child was born, whom we preferred to raise in Japan. To make that transition, I became a lecturer at the Institute for Biomedical Engineering of the Consolidated Research Institute for Advanced Science and Medical Care at Waseda University (ASMeW).

AsMeW is a time-limited institute, established as the leading body of the Super COE Program in Japan. It brings together an interdisciplinary team of around 100 researchers from different fields, mainly from science and engineering. The team was brimming with energy to start something ingenious. Aside from research, I learned a great deal about research management, as well as science and technology policies. For instance, we had the chance to discuss a plan for a large-scale project with Katsuhiko Shirai (the former president of Waseda University), who was the director of the Institute at the time, along with other key faculty members.

A joint project with Germany during my time at ASMeW

During my two years at ASMeW, we began a research project focused on tiny, unique RNAs called microRNAs. Unlike messenger RNAs, microRNAs do not code for proteins, but they were found to function in regulating gene expression. In order to investigate the roles of these microRNAs in muscle, we carried out an exhaustive examination of the 1,000 microRNAs that were known at the time and found that about 200 of them are present in muscle. Then, we extracted several microRNAs that play different roles in slow and fast muscles, and analyzed their functions using genetically modified mice and cultured cells.

This research project took several years, during which time my laboratory moved to the Graduate School of Medicine at The University of Tokyo. We managed to discover that one of the microRNAs that we had focused on was involved in inhibiting muscle atrophy. Another microRNA was discovered to inhibit the gene expression (mentioned above) linked to the transformation of PGC-1α, the skeletal muscle that I worked on in the US, into slow muscle. These reports were the first to clarify that microRNA plays an important role in skeletal muscle plasticity.

With fellow laboratory members of the Graduate School of Medicine at The University of Tokyo

Having spent eight and half years at The University of Tokyo, I returned to Waseda in April 2016 as Professor at the Faculty of Sport Sciences, where I am today. I hope to ensure the nurturing of dedicated sports-oriented students in the field of sports science, which is different from the medical sciences and engineering fields that I have spent most of my research career in so far. I am currently aiming to foster researchers who can advance sports science and health science by adopting the methodologies of molecular and cellular biology that I have studied.

Takayuki Akimoto
Professor, Faculty of Sport Sciences

Takayuki Akimoto completed his Ph.D. in medical sciences at University of Tsukuba in 2000. He served as Research Associate of the Graduate School of Arts and Sciences at The University of Tokyo (2000–2004), Research Associate at Duke University Medical Center (2003–2006), Lecturer at the Institute for Biomedical Engineering of Waseda University (2005–2007), Lecturer of the Graduate School of Medicine at The University of Tokyo (2007–2016), and Visiting Professor at the University of Padua (2010–2011). Professor Akimoto has held his current position since April 2016. He specializes in muscle biology and mechanobiology. Among the awards Professor Akimoto has received are the Junior Researcher Award from the Japanese Society of Physical Fitness and Sports Medicine (2004), Research Recognition Award from the American Physiological Society (2004), Superior Achievement Award from ASMeW (2006), and Waseda Research Award (for high-impact publication) (2016).