From surprise to solution
Following their surprising discovery, the team took a closer look at the muscles’ stem cells. They saw that applying a mechanical load to muscle, as happens during mechanotherapy treatment, influences muscle cell behavior via several molecular “mechanotransduction pathways” that also affect stem cells.
“We showed that although aged stem cell behavior was disrupted by the elevated inflammation, they were still able to ‘feel’ the mechanical forces of loading as we demonstrated by the activation of these pathways,” said first author Stephanie McNamara, a graduate student on Mooney’s team who is currently enrolled in the joint Harvard/MIT M.D.-Ph.D. program. “This actually was what prompted us to ask whether controlling inflammation might enable these cells to respond to the mechanical stimuli — and indeed it did.”
The team found that administering anti-inflammatory therapy in the form of the steroid hormones glucocorticoids alongside mechanotherapy suppressed key pro-inflammatory pathways and reduced overall inflammation levels in injured aged muscle to those seen in injured young muscle. Yet at a cellular level, the muscle cells continued to experience mechanotransduction, and by removing the negative impacts of inflammation, injured aged muscles could positively respond to the robot-delivered mechanical loading.
“It is well-known that, with age, many of the normal processes of muscle healing and inflammation change. It’s important to question whether the same mechanisms seen in studies performed in young animals stay the same as the body ages,” McNamara said. “By leveraging what we learned in this study and our previous work and combining it with growing expertise in wearable soft robotic systems, we believe that in the future personalized mechanotherapeutic approaches can be developed to heal injuries across all ages.”
Other authors on the study are additional members of Mooney and Walsh’s groups, including Bo Ri Seo, Benjamin Freedman, Emily Roloson, Jonathan Alvarez, C.T. O’Neill, and Herman Vandenburgh, professor emeritus at Brown University, Providence, Rhode Island.
The study was funded by the National Institute of Dental and Craniofacial Research (under grant #R01DE013349), National Science Foundation (under grant #DMR-1420570), National Institute of Arthritis and Musculoskeletal and Skin Disease (under grant #F31AR075367), National Institutes of Health (under grant #K99AG065495), National Institute of General Medical Sciences (under award #T32GM007753 and T32GM144273), as well as an AR3T Regenerative Rehabilitation pilot grant.