Controlling inflammation allows injured aged muscles to recover, which bodes well for the future of mechanotherapies.
For decades, mechanical forces — including massage — have been used to stimulate tissue healing as a form of physical therapy. However, the biological basis and optimal settings for noninvasive mechanotherapies remain unknown, particularly in elderly patients.
A new multidisciplinary study looked into whether elderly people could benefit from tailored mechanotherapy for severely injured muscles in the same way that young people could.
The study was performed by researchers at the Wyss Institute for Biologically Inspired Engineering and the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), led by Wyss core faculty member David Mooney in collaboration with associate faculty member and Paul A. Maeder Professor of Engineering and Applied Sciences Conor Walsh. Previously, the researchers used Walsh’s lab to create a robotic mechanotherapy device that works like a high-tech massage gun. This technology allowed the team to precisely deliver mechanotherapy to injured muscles in mice, allowing them to measure the biological effects.
The researchers discovered that mechanotherapy accelerated muscle healing in young animals by reducing inflammation. The same treatment, however, had the opposite effect on aged muscle — the settings that promoted healing in young muscle exacerbated injury in old muscle.
In their search for an explanation, the researchers discovered that mechanotherapy increased inflammation in aged muscle, impeding normal healing by interfering with the behaviour of muscle stem cells, a subset of cells responsible for replacing damaged muscle tissue.
The researchers then wondered if controlling inflammation while also delivering mechanotherapy could aid in the healing of aged muscles. They found that this was indeed the case: combining mechanotherapy with anti-inflammatory treatment significantly improved healing in aged muscles and was superior to anti-inflammatory treatment alone. This study, which was published in the journal Science Robotics, opens up an exciting, noninvasive therapeutic avenue for elderly patients.
“Our findings highlight critical differences in how muscle stem cells and immune cells respond to mechanical forces in the context of age, as well as how upregulated inflammation further compromises the function of aged stem cells required for muscle regeneration,” said Mooney, who is also the Robert P. Pinkas Family Professor of Bioengineering at SEAS. “Muscle mechanotherapies are unlikely to be ‘one-size-fits-all.'” To reap their benefits, they must be tailored to patient populations, and modulating inflammation will be especially important for the elderly.”
From astonishment to a solution
Following their unexpected discovery, the researchers examined the muscles’ stem cells in greater detail. They discovered that mechanically loading a muscle, as occurs during mechanotherapy treatment, influences muscle cell behaviour via several molecular “mechanotransduction pathways” that also affect stem cells.
We demonstrated that, despite the fact that aged stem cell behaviour was disrupted by the elevated inflammation, they were still able to ‘feel’ the mechanical forces of loading, as evidenced 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. programme. “This is what prompted us to wonder whether controlling inflammation might allow these cells to respond to mechanical stimuli — and it did.”
The researchers discovered that combining anti-inflammatory therapy with mechanotherapy in the form of the steroid hormones glucocorticoids suppressed key pro-inflammatory pathways and reduced overall inflammation levels in injured aged muscle to those seen in injured young muscle. At the cellular level, however, the muscle cells continued to undergo mechanotransduction, and by removing the negative effects of inflammation, injured aged muscles were able to positively respond to the robot-delivered mechanical loading.
“It is well known that many of the normal processes of muscle healing and inflammation change with age.” “It’s critical to ask whether the same mechanisms seen in studies on young animals remain the same as the body ages,” McNamara said. “By leveraging what we learned in this study and previous work and combining it with growing expertise in wearable soft robotic systems, we believe that personalised mechanotherapeutic approaches to healing injuries across all ages can be developed in the future.”
Members of Mooney and Walsh’s groups also contributed to the study, including Bo Ri Seo, Benjamin Freedman, Emily Roloson, Jonathan Alvarez, C.T. O’Neill, and Herman Vandenburgh, professor emeritus at Brown University in Providence, Rhode Island.
The study was supported by the National Institute of Dental and Craniofacial Research (R01DE013349), the National Science Foundation (DMR-1420570), the National Institute of Arthritis and Musculoskeletal and Skin Disease (F31AR075367), the National Institutes of Health (K99AG065495), the National Institute of General Medical Sciences (T32GM007753 and T32GM144273), and an AR3T Regenerative Rehabilitation pilot grant.
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