Tendons are stretchy bands of connective tissue that connect muscles to bones. A new study shows, a variant of a gene that encodes an ion channel in tendons that is sensitive to mechanical pressure, can make mice run faster and jump further. This genetic variation that widens tendons, enlarges collagen fibril diameter, and increases compliance and elastic energy, is common in individuals of African descent, the authors note.
The findings were published in the journal Science Translational Medicine “The mechanosensitive ion channel PIEZO1 is expressed in tendons and regulates physical performance” on June 1, 2022. The authors show the frequency of the genetic variation (PIEZO1 E756del) was higher in sprinters than in nonathletic individuals in a small Jamaican group, which suggests that the variant may play a similar role in humans.
Senior author of the study, Hiroshi Asahara, MD, PhD, professor of Molecular Medicine at Scripps Research, said, “Based on our data, PIEZO1 plays a key role in the properties of tendons. It also has the potential to be a therapeutic target for treating age-related declines in physical performance. The data suggested that what we observed in mice might hold true in humans but more work is needed to understand the full role of PIEZO1 in human tendons.”
The PIEZO1 ion channel was discovered in 2010 by Ardem Patapoutian, PhD, a Howard Hughes Medical Investigator, professor at Scripps Research, and an author of the current study, who won the 2021 Nobel Prize in physiology and medicine for discovering the protein and showing how the related protein, PIEZO2, enables touch and proprioception.
Patapoutian said, “This new role of PIEZO1 in tendon biology, identified in mice, underscores just how important this group of ion channels is. We’re discovering more possible new roles of PIEZOs in health and disease as we keep studying them.”
Earlier studies have shown PIEZO1 to play a role in the development of blood vessels, heart, bone and immune cells. In addition, a variant of the gene protects against malaria but may predispose people to higher levels of iron in the blood, as reported by Patapoutian’s group. Previous studies have also shown, PIEZO1 regulates Mohawk, a gene discovered by Asahara’s team, that plays a role in tendon differentiation.
In the current study, Asahara’s group investigates how the PIEZO1 gene variant that was found to provide resistance to malaria in humans (E756del variant) by Patapoutian’s group, impacts tendon structure and function. Asahara’s team modeled the genetic variation in mice and had earlier shown that the mutation R2482H (that changes an arginine residue to histidine at the 2482nd residue of the protein), also provided resistance to malaria, like the human variant. The genetic change causes the ion channel to close more slowly when activated.
Ashara’s group confirmed that the PIEZO1 genetic variation has no effect on the cellular architecture of muscle or nerve, but only altered cells in tendons (tenocytes). Mice carrying the variant in all cells of the body or in tendons alone, jumped further and could run faster than control mice.
“These results suggested that this PIEZO1 mutation is enhancing tendon tissue in a way that really impacts physical ability,” says Ryo Nakamichi, MD, PhD, a former member of the Asahara lab who is now an orthopedic surgeon at Okayama University in Japan, and the first author of the paper.
The authors demonstrate PIEZO1 in tendons enables calcium to flow in and out of cells. Altered flow of calcium changes the expression of genes, including Mohawk, involved in tenocyte development. Asahara’s team intends to target PIEZO1 to treat tendon injuries and tackle age-related decline in mobility, in future studies.
The study was supported by funding from the Japan Agency for Medical Research and Development, JSPS KAKENHI and the National Institutes of Health.