As muscles age, their cells lose the ability to regenerate and heal after injury. Cornell Engineering researchers have created the most comprehensive portrait to date of how that change, in mice, unfolds over time and across the complicated architecture of muscle tissue.
"The fundamental question that drove the initial study was really a question that had perplexed the skeletal muscle biology community," said Ben Cosgrove, associate professor in the Cornell Meinig School of Biomedical Engineering and the paper's senior author. "Does the decline in regeneration seen in old muscles come from changes to the stem cells that drive the repair process themselves, or does it come from changes in the way that they are instructed by other cell types?"
In their study, "Transcriptomic Analysis of Skeletal Muscle Regeneration Across Mouse Lifespan Identifies Altered Stem Cell States," published Nov. 22 in Nature Aging, researchers sampled cells from young, old and geriatric mice at six time points after inducing injury via a variant of snake venom toxin. They identified 29 defined cell types, including immune cells that exhibited differences in their abundance and reaction time between age groups, and muscle stem cells that self-renew in youth but stall out as muscles age.
The detailed assessment of many cell types over time showed discoordination in the process of muscle repair in older mice. Many immune cells, which coordinate tissue repair, show up at the wrong time.
"There's too many of them or too few of them," Cosgrove said. "The immune cells are playing the wrong music. They're out of step with each other in the older muscles."
The research team used a novel method to evaluate senescence - when a cell can no longer divide.
"We developed what we are calling a transfer-learning based method," said lead author Lauren Walter, Ph.D. '24, a doctoral student in Cosgrove's lab at the time of the study. "We used an existing list of genes to score a cell's senescence status and then used that methodology to evaluate senescence across age and regeneration time point."
The study provides a better understanding of the interactions between cell types and how they induce senescence, which could inform efforts to develop drugs that target senescent cells.
"What our dataset provides is a rich template to really investigate what would be the benefits or detriments of removing senescent cells from tissues," Cosgrove said. "The reason why people do this in mouse models is that we can really test out those hypotheses directly so that we can better understand the benefits of targeting senescent cells to improve the repair processes in older individuals."
Co-authors include doctoral students Jessica Orton, M.S. '23, and Ioannis Ntekas, M.S. '23; Viviana Maymi, a joint DVM/Ph.D. student; Ern Hwei Hannah Fong, research technician in Biomedical Engineering; Brian Rudd, professor in the Department of Microbiology and Immunology in the College of Veterinary Medicine; Iwijn De Vlaminck, associate professor in the Department of Biomedical Engineering; and Jennifer Elisseeff, of Johns Hopkins University.
The research was supported by the U.S. National Institutes of Health, the Bloomberg~Kimmel Institute and the Morton Goldberg Professorship.
