Developing a drug that prevents a vicious cycle due to lack of movement to elucidate the mechanism that reduces muscles if you do not move your body

If you lose your muscles, you will not be able to exercise, and if you can't exercise, your muscles will decrease.

Research is based on Kobe University Kobe University Graduate School of Medicine, Division of Diabetes and Endocrinology Faculty of Medicine, Professor Hiroaki Waki of Nagoya University Molecular cellology, and Associate Professor Takahiro Adachi of Tokyo Medical and Dental University.The research results were published online in "Journal of Clinical Investation".

When muscles decrease, not only decreases motor skills, but also more susceptible to various diseases, such as type 2 diabetes and obesity, and shorten life.Sarcopenia, which is particularly aging and reduces motor skills, is a major problem in Japan, where the number of elderly people continues to increase.

It is known that exercise and training increase muscle mass, and if it does not move, muscle mass is reduced.If you lose your muscles, it will be difficult to exercise, and if you do not exercise, you will have a vicious cycle in which muscles decrease further.

In addition, being forced to rest on bed due to hospitalization and surgery, such a vicious cycle may accelerate at once.

It is required to develop a way to break such a vicious cycle.However, the mechanism that reduces muscles if it does not move is not well understood, and the hypothesis has been proposed that muscles decrease because the exercise that increases muscle increases.

If the muscles do not move, the calcium concentration in the cell decreases

In this study, the research group discovered that if muscles were not moved, the calcium concentration in cells would decrease, which would trigger muscles.He also concluded the role of three proteins that work importantly.

First, it was discovered that if the mouse legs were not moved due to the disconnection of the motor nerves and the fixation of the gyps, the muscle mass would decrease and that the KLF15 protein increased with muscles.

When I made a mouse that lost KLF15 with just muscles, I found that this mouse did not reduce muscle even if I did not move my legs.In other words, it was revealed that the increase in KLF15 if it did not move was the cause of reducing muscles.

Next, we examined what kind of mechanism would increase KLF15 if it did not move.As a result, it was found that a decrease in calcium concentration in cells was the cause.

Calcium concentration decreases causes KLF15 to increase muscle

Usually, any cells have low calcium concentration in cells.When stimulation is applied to the cells, the calcium concentration rises several tens to hundreds of times, triggering the reaction of various cells.

The research group has developed a very sensitive biological imaging, and discovered that if the muscles do not move, the calcium concentration in muscle cells, which is maintained low, will be even lower.

Biological imaging is the latest technology that captures various reactions in biological organs and cells in an image of the living thing as the living thing is alive.

He found that this increased KLF15 and caused muscle mass.It is known that the rise in calcium concentration in the cells can trigger a variety of cells, but the reaction caused by a decrease in calcium concentration is hardly known.

Furthermore, examining why calcium concentration in the cells decreases, it was found that the protein Piezo1 was reduced by muscle.Piezo1 is a protein that works like a "window" that captures calcium from outside the cell to cells.

When the mouse muscles were reduced, Piezo1 had the same change as when the legs were not moved, such as a decrease in calcium concentration and a decrease in muscle mass, even if the mouse was moving.

Develop an effective treatment for muscle reduction

Finally, the increase in KLF15 has increased the protein called protein IL-6, which also has the effect of reducing muscle.It was found that administering an antibody that suppresses the function of the IL-6 to the mouse will not reduce muscle even if the legs are not moved.

The IL-6 is a protein that works importantly in various inflammation control.Antibodies that suppress the function of IL-6 are used as treatments for new colona and rheumatoid arthritis.

Based on these results, if you do not move, your muscles will decrease Piezo1, which will reduce the level of intracellular calcim, which will increase KLF15, which will increase the muscle mass in which KLF15 increases IL-6.Was revealed for the first time.

Consideration using muscle samples of patients who had reduced muscle by fixing gyps due to fractures also provided evidence that Piezo1, KLF15, and IL-6 were working.

"Currently, there is no effective treatment for muscle reduction. There are concerns about the side effects of lowering immunity in treatment using antibodies of IL-6, but if you can develop drugs that act on Piezo1 and KLF15, it will be groundbreaking.Researchers say that it may be a treatment for muscle reducing, "said researchers.

Already, Professor Ogawa and his colleagues have received the support of the Japan Medical Research and Development Agency, and has begun the development of such drugs.

Kobe University Graduate School of Medicine, Graduate School of Medicine, Faculty of Medicine, Faculty of Medicine, Endocrinology A Piezo1/KLF15/IL-6 AXIS MediaTes Imobilization-Induced Muscle Atrophy (Journal of Clinical Investation March 15, 2022)