Tokyo Medical and Dental University, The Scripps Research Institute research group clarifies role of mechanosensitive ion channel PIEZO1 in individuals

A research group led by Professor Hiroshi Asahara and Adjunct Lecturer Ryo Nakamichi of the Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Associate Professor Noriyuki Fuku of the Graduate School of Sports and Health Science, Juntendo University, and Associate Professor Takayuki Nonoyama of the Faculty of Advanced Life Science, Hokkaido University, in collaboration with Hiroshima University, Okayama University, The Scripps Research Institute, the University of Brighton and the National Commission on Science and Technology (Jamaica), announced that they have shown that homeostatic activation of the mechanosensitive ion channel PIEZO1 in tendon cells alone improves athletic performance in mice. The muscle tissue in the same mice did not differ from those of wild mice, demonstrating that the improved athletic performance depended on tendons rather than muscles. These findings are expected to contribute to the development of training methods to promote healthy longevity and athletic performance. The findings were published in the June 1 issue of the international science journal Science Translational Medicine.

Tendons are the tissues that connect skeletal muscle to bone and function as transmitters that receive signals from surrounding tissues and transmit them to the skeletal muscle. Ligaments also function similarly as a connective tissue between bones. These tissues have a low capacity for self-healing, and once damaged, do not fully recover, thereby reducing athletic performance. However, it is not well known how athletic performance is exerted by tendons and ligaments. Accordingly, it is believed that gaining an understanding of the mechanisms in these tissues is important for extending healthy life spans.

In previous research, the research group found that MKX (Mohawk) is a master transcription factor in tendon differentiation. Their research clarified that MKX is essential for tendon differentiation, that exercise increases MKX function and makes tendons stronger and thicker, and that MKX is important for the maintenance of normal function of tendon and ligament tissues and for the anabolic effects of mechanosensitivity in tendon tissue. However, the question of how the cells detected the mechanosensitivity was unclear.

Accordingly, for this study, the research group focused on the high expression of PIEZO1, known as a mechanosensitive receptor, in tendon cells. Furthermore, because people who genetically carry a variant (E756del) with particularly high PIEZO1 sensitivity are common among West Africans (the PIEZO1 homeostatic mutation), the group also focused on the overlap between the distribution of such individuals and the distribution of Olympic 100-meter record holders. The group compared the rates of the variant among record-holding sprinters in Jamaica, a country with many people and sprinters of West African origin, with those among a population-matched nonathletic control cohort. This comparison showed that the rate of the variant was significantly higher among Jamaican sprinters than the general cohort.

The group then generated mice with homeostatic activity of PIEZO1 throughout their bodies (PIEZO1 systemic-mutant mice) and compared their physical performance with wild mice.

Accordingly, the jumping and running ability of the PIEZO1 systemic-mutant mice was found to be greater. For example, whereas wild mice were able to jump 27 cm, the PIEZO1 systemic-mutant mice were able to jump 45 cm.

In order to clarify the body part in which the PIEZO1 mutation is responsible for this improvement in locomotion, tendon-specific and muscle-specific PIEZO1 mice (10 males and 10 females each) were generated in addition to the systemic-mutation mice and compared to wild mice.

This comparison showed that jumping and running ability was only improved in the systemic-mutation and tendon-specific mice. Compared to the average jump distance of 31.5 cm for wild males, males with the tendon specific mutation could jump 43 cm, while females with the mutation could jump 44 cm compared to 26 cm for wild females.

When the relevant tissues were actually examined, the expression of tendon-related genes, including the transcription factor MKX, was found to be higher in both the systemic-mutation and tendon-specific mice, while hypertrophy in the tendon tissue was also confirmed. The group further confirmed that the increase in tendon tissue and jumping ability could be obtained even when the PIEZO1 variation was inserted into adult mice, showing that the finding could potentially be applied to medical treatments as well. Meanwhile, there was no difference in ability between muscle-specific mutants and wild mice.

The group found by measuring the mechanical properties of the tendon-specific tissue that it was softer and more elastic than that of the wild mice. Meanwhile, further observation found that the source of the jumping ability of the tendon-specific mice was the elastic energy of the Achilles tendon. To date, it had long been assumed that jumping ability and the capability for bursts of speed depended on muscles, but these findings clarified that in fact they depend on mechanosensitivity of the tendons.

Moving forward, the group aims to carry out further research for extending life expectancy, including the development of manmade tendons and medicines to maintain or improve tendon homeostasis.