Northwestern Medicine investigators have identified a protein that can enhance the repair of acute injuries by more than 50 percent, according to a study recently published in the Journal of Clinical Investigation.
By using microscopy, the scientists observed that annexin A6, a protein previously identified as a genetic modifier for muscle injury and disease, facilitated muscle repair in mouse models with acute muscle injuries.
Specifically, the protein stimulated the formation of a scab, or “repair cap,” at the site of laser-induced injury through increased expression and decreased the amount of injury associated calcium ions within myofibers in the damaged muscle cells, according to lead author Alexis Demonbreun, PhD, research assistant professor of Pharmacology, and senior author Elizabeth McNally, MD, PhD, the Elizabeth J. Ward Professor of Genetic Medicine and a professor of Medicine in the Division of Cardiology.
“We only really got interested in this protein in the first place because we had mapped the gene as a modifier, so that’s what made us actually say this was a good pathway, let’s think about what we know about the pathway, let’s learn more about the pathway and let’s think about how we can develop a drug around it,” said McNally, who is also a professor of Biochemistry and Molecular Genetics and the director of the Center for Genetic Medicine.
In the current study, the scientists introduced a gene that codes for annexin A6 directly into the muscle to stimulate the production of the protein. This approach then caused the overexpression of the annexin A6, which in turn stabilized the muscle and accelerated healing after laser induced injury. The authors then injected the annexin A6 protein into the muscle and observed the effects via microscopy.
The authors found that acute muscle repair in the mice was improved by over 50 percent. Additionally, the increased expression of annexins in the muscle fibers also decreased injury-associated calcium accumulation within the myofibers, and this increase in calcium intensified the injury response. Injecting annexin A6 also reduced muscle leak and injury in a mouse model of muscular dystrophy, indicating that the approach may help treat that disease.
“We were super excited to observe that this could improve acute injury, which is in healthy tissue, and we can enhance repair,” Demonbreun said. “We’ve now shown in two different models, of chronic muscle injury and muscular dystrophy, that this reduces leak of those muscles.”
Although the research is in its beginning stages, Demonbreun noted that annexin A6 shows significant potential as a therapeutic tool for resealing injured cell membrane in muscles.
The next steps for their research are to determine what mechanisms to use to deliver the treatment, where to inject annexin A6, and how often the protein therapeutic might need to be delivered to a muscle to guarantee the best clinical outcomes in patients, including those with muscular dystrophy.
Additionally, the authors noted that the study would not have been possible without advances made in microscopy over the last decade.
“Northwestern has an outstanding microscopy core facility which really enabled this research,” McNally said. “The objectives have gotten better. The computer analysis of images, all of these things have made it so that we can see things with much, much higher resolution than what we ever could.”
The research is one of two drug-discovery projects currently funded by Lakeside Discovery, LLC, a collaboration launched in June 2018 between Northwestern University and healthcare investment company Deerfield Management, in which Deerfield has provided up to $65 million of targeted funding for promising biomedical research projects specifically at Northwestern.
