Lipid mediator Maresin 1 helps improve muscle regeneration

How lipid mediators -- potent regulators of the immune response after an injury -- varied with the acute loss of a large volume of skeletal muscle, also known as volumetric muscle loss (VML) is the focus of new research from the University of Michigan.

 The work -- led by U-M’s Carlos Aguilar, Ph.D., associate professor of biomedical engineering, along with graduate students Jesus Castor-Macias and Jacqueline Larouche -- recently was published in the journal eLife.

VML is a devastating type of injury that results in exacerbated and persistent inflammation followed by scarring, or fibrosis. The mechanisms that mediate the magnitude and duration of the inflammatory response and ensuing fibrosis after VML remain understudied, and as such, the development of regenerative therapies has been limited. 

“My lab has a long-standing research interest in this area of muscle trauma, in part because this is a pervasive injury that happens more frequently than people think,” Aguilar said.

“VML is responsible for over 90% of all muscle conditions that lead to long term disability and there are no therapies that have successfully translated into the clinic for this trauma. We tried to understand some of the cellular and molecular mechanisms that develop after this type of trauma occurs to generate and test new therapeutic modalities.”

Scarring and muscles

Aguilar explained that when VML occurs, a dysregulated immune response drives a stiff and dense fibrotic scarring that turns off the muscles’ ability to heal themselves or regenerate.

“We were intrigued with this relatively new class of signaling molecules called lipid mediators that have previously been shown to have potent effects on immune reactions,” he said. In particular, the team focused on a derivative of omega-3 fatty acids called Maresin 1.

“We focused on Maresin 1 because this lipid mediator has been found to attenuate the behavior of inflammatory cells like neutrophils and macrophages,” he added. 

“When we delivered Maresin-1 after VML, we found that the number of infiltrating neutrophils and macrophages and concomitant fibrosis went down and that muscle force went up.”

Potential therapeutic

The long term implications of the study point to the role of this class of signaling molecules as a potential therapeutic for severe muscle trauma. 

“I think these results set the stage to explore immunomodulatory treatments to enhance muscle generation.”

Aguilar acknowledged the work of graduate students Castor-Macias and Larouche. “They are two amazing students who really drove this research,” he said. “I am so proud of them and how creative they were in using new mouse models and technologies to address these questions.”

Additional authors include Emily Wallace, Bonnie Spence, Alec Eames, Pamela Duran, Benjamin Yang, Paula Fraczek, Carol Davis, Susan Brooks, Krishna Rao Maddipati, James Markworth, and Carlos Aguilar

Citation: “Maresin 1 repletion improves muscle regeneration after volumetric muscle loss,”, eLife (2024). DOI: 10.7554/eLife.86437

Written by Michele Santillian, communications manager for U-M's biomedical engineering department

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