Long used as a method of physical therapy to help heal injured muscles, mechanotherapy is the idea of applying mechanical stresses to stimulate tissue healing. However, there is currently a lack of knowledge regarding the molecular underpinnings and ideal settings for mechanotherapy, particularly with regard to senior patients. Elderly patients stand to gain significantly from an efficient, non-invasive musculoskeletal therapy strategy given the well-known reduction in healing capacity that happens with age.
This gap in our understanding of the efficiency of mechanotherapy in aging muscle is filled by a recent multidisciplinary study. 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, Ph.D. in collaboration with Associate Faculty member and Paul A. Maeder Professor of Engineering and Applied Sciences, Conor Walsh, Ph.D.
In earlier work, the partners created a robotic mechanotherapy device that works like a highly advanced massage gun using Walsh’s Lab’s expertise in wearable robotic systems. The team was able to quantify the biological effects of non-invasive mechanotherapy by precisely delivering it to mice with wounded muscles thanks to technology. The researchers discovered that mechanotherapy expedited muscle recovery by reducing inflammation after injury by using this device to tailor the amplitude, duration, and frequency of force delivered to the muscles of young animals.
Using this device on aged muscle, the researchers discovered that the same mechanotherapy treatment that promotes faster injury recovery in young muscle really has the opposite impact with aging. The settings that encouraged injury recovery in young muscles actually made the injury worse in elderly muscles.
To understand these findings, the team discovered that mechanotherapy, rather than reducing inflammation in aged muscle, amplified it. This, in turn, interfered with the behavior of muscle stem cells, a subset of cells that are in charge of repairing damaged muscle tissue, which ultimately hampered the normal healing process. These results prompted the researchers to investigate if administering mechanotherapy while also reducing inflammation could promote repair in aging muscles. They discovered that this was in fact the case, with mechanotherapy greatly enhancing recovery in aging muscles and outperforming anti-inflammatory treatment alone. This study, which was published in Science Robotics, creates a novel non-invasive therapeutic pathway for the recovery of muscular damage in senior people.
“Our study highlights critical differences in how muscle stem cells and immune cells respond to mechanical forces in the context of age, and how upregulated inflammation additionally compromises the function of aged stem cells needed for the regeneration of old muscles,” said Mooney who also is the Robert P. Pinkas Family Professor of Bioengineering at SEAS. “Muscle mechanotherapies likely thus won’t be a ‘one-size-fits-all.” To realize their benefits, they will have to be tailored to patient populations, and specifically for aged individuals, it will be key to modulate inflammation.”
Following their surprising discovery that mechanotherapy alone actually hinders the normal regeneration process of aged muscles by interacting with the immune system, the team took a deeper look at the muscles’ stem cells. Applying a mechanical load to muscle, as is done 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, who is a graduate student on Mooney’s team and currently enrolled in the joint Harvard/MIT MD-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 researchers discovered that providing glucocorticoids, an anti-inflammatory drug, together with mechanotherapy blocked important pro-inflammatory pathways and brought the level of total inflammation in injured elderly muscle to that of injured young muscle. However, at the molecular level, muscle cells continued to undergo mechanotransduction. By reducing the detrimental effects of inflammation, wounded, aging muscles may respond favorably to the mechanical stimulus given by the robot.
“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 says. “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.”
“This discovery that a non-invasive mechanotherapy can stimulate muscle repair in the elderly when combined with anti-inflammatory therapy opens an entirely new path for regeneration and repair in older populations. Mechanotherapies clearly have immense potential to change the lives of patients, but it is truly cross-disciplinary collaborations, such as the one between Dave Mooney’s and Conor Walsh’s groups at the Wyss Institute, that set the stage for advancing them into clinical realities,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.
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