Digging deep for differences in Duchenne muscular dystrophy

DALLAS – December 21, 2020 – The UT Southwestern research team has cataloged gene activity in the skeletal muscle of mice, comparing healthy animals to those carrying a genetic mutation that causes Duchene muscle damage ( DMD) in humans. The findings, recently published online in PNAS, that could lead to new cures for this devastating degenerative disease and insight into factors that affect muscle development.

Understanding the activity of genes can shed light on pathologies that affect different tissues in the body. However, says Rhonda Bassel-Duby, Ph.D., professor of molecular biology at UTSW, studying skeletal muscle has been a challenge because of a major difference from other types of tissue; instead of containing a single nucleus that controls the activity of genes, skeletal muscle fiber can contain hundreds of nuclei. And it was not known which genes were activated in all of those nuclei, making it clear how gene expression differentiates between healthy skeletal muscle tension and a tumor affected by DMD.

To answer these questions, Eric Olson, Ph.D., chair and professor of molecular biology at UTSW, Bassel-Duby, and their colleagues separated the anterior tibialis, a muscle in mice-like one in people running down there. They took these samples from both healthy animals and from a mouse model of DMD that they generated using gene editing technology to introduce mutations that often cause DMD in humans. The researchers then removed muscle tension from the two sets of animals, In muscle strains from both groups, the scientists identified 14 types of nuclei based on similar gene profiles. These nuclei appear to perform various functions based on their primary gene activity, such as maintaining mature muscles, communicating with neurons or tendons, or regenerating new muscle fibers. The researchers also identified nuclei of other types of cells, such as smooth muscle cells, endothelial cells, cells that produce fat or connective tissue, and immune cells called macrophages.

When the researchers compared numbers of the 14 nuclei between healthy mice and DMD, they found significant differences. For example, compared to the healthy animals, those with DMD had significantly fewer mature muscle nuclei. Instead, they had many more macrophages, reflecting the inflammation present in DMD muscles, as well as a division of regenerative cells that are not present in healthy tissue at all. The nuclei involved in interfacing with zero cells and tendons were the largest differences in gene expression between the two groups, suggesting that DMD is the most influential. on them of all kinds of nuclei.

In addition, almost all muscle nuclei isolated from the DMD animals had increased gene activity in the ubiquitin pathway, which tags proteins for contamination, as well as increased activity. height of genes involved in apoptosis, or cell death – indicating muscle contamination that signals DMD.

Bassel-Duby notes that the study has several key limitations: For example, the technology used did not reveal where the muscle nuclei were located within the skeletal muscle, which may providing a valuable loan to how nuclei can communicate with each other and influence gene function. It is not yet known whether repairing the genetic predisposition that causes DMD returns normal gene activity. She and her colleagues plan to explore both of these issues in future studies.

By developing a better understanding of how muscle fiber works both in healthy tissue and with disease, she adds, researchers could eventually learn to manipulate gene activity to the best standards. As a more immediate goal, identifying differences present in DMD patients may lead to new targets for treatment.

“Identifying specific gene functions in these nuclei could give us new ideas for previously neglected therapies,” Bassel-Duby says. “Ultimately, we could find ways to ultimately to prevent these patients’ muscles from shrinking and improve their quality of life. “

“Our study introduces new insights into the molecular bases in Duchenne muscular dystrophy at an unprecedented level of resolution and highlights a collection of genes and signaling pathways with key roles in this disease,” Olson explains “This work opens the door to new approaches to reducing the serious pathology of this disease through pharmacological or genetic interventions.”

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Other UTSW researchers who contributed to this study include Francesco Chemello, Zhaoning Wang, Hui Li, John R. McAnally, and Ning Liu. Olson, also director of the Hamon Center for Regenerative Science and Medicine and co-director of General Paul D. Wellstone of the Muscular Dystrophy Collaborative Research Center, holds the prestigious Pogue Chair in Research into Cardiac Birth Problems Distinguished Robert A. Welch Chair in Science, and Annie and Willie Nelson Professor in Stem Cell Research.

This study was supported by funds from the National Institutes of Health (HL130253 and AR067294), Wellstone Muscular Dystrophy Center (U54 HD 087351), Robert A. Welch Foundation (donation 1-0025), American Heart Association, and Harry S. Moss Heart Trust (19PRE34380436).

UT Southwestern, one of the leading academic medical centers in the country, offers advanced biomedical research with exceptional clinical care and education. The institute’s faculty has received six Nobel Prizes, and there are 23 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute researchers. The full-time faculty of more than 2,500 relies on advanced medical advances and is committed to rapidly translating science-led research into new clinical therapies. UT Southwestern physicians provide care in approximately 80 specialties to more than 105,000 hospital patients, nearly 370,000 emergency room cases, and monitor approximately 3 million outpatient visits each year.