Getting out of bed shouldn’t feel like a high-stakes gamble. But for millions of older adults battling sarcopenia, that’s exactly what it becomes. The progressive loss of muscle mass doesn’t just make daily tasks harder. It sets off a cascade: falls, fractures, hospitalizations, and often a swift, steep decline that doctors struggle to reverse.
Now researchers at Sanford Burnham Prebys have identified a key player in the aging muscle story. Their findings, published December 5, 2025, in Communications Biology, reveal how a protein called tenascin-C helps maintain the pool of muscle stem cells needed for efficient repair. When tenascin-C levels drop with age, so does the muscle’s ability to heal itself.
“It is absolutely crucial that we are able to develop strategies to maintain muscle as we age,” said Alessandra Sacco, dean of the Sanford Burnham Prebys Medical Discovery Institute Graduate School of Biomedical Sciences.
Sacco noted that progressive loss of skeletal muscle mass and function are indicators of poor survival in patients, making the discovery particularly relevant for an aging population.
The Protein Behind the Curtain
Think of tenascin-C as a conductor for the cellular ensemble that rebuilds damaged muscle. The protein sits in the gel-like scaffold between cells, the extracellular matrix, where it coordinates the behavior of muscle stem cells. These cells remain dormant in healthy muscle, waiting in their sublaminar niche. When injury strikes, they spring into action, multiplying and either replenishing the stem cell pool or differentiating to repair damaged tissue.
The research team’s earlier work on how muscles develop before birth led them to tenascin-C. Lale Cecchini, a staff scientist in the Sacco lab and co-first author of the study, explained that TnC was among the genes specifically elevated at the prenatal stage, when organisms potently express proteins used to build muscles they’ll need as adults.
The organism doesn’t throw away those developmental blueprints after birth. When muscle gets injured, it reactivates the same pathways that built the tissue in the first place. Tenascin-C normally stays quiet in healthy adult muscle, but levels spike rapidly after injury to kick-start regeneration programs. The protein begins appearing three days after injury and peaks at five days, according to the team’s experiments.
To understand where tenascin-C comes from during muscle repair, the scientists looked at which cells were producing it. They found that support cells called fibro-adipogenic progenitors were secreting the protein. These cells play a crucial role during muscle regeneration, depositing extracellular matrix components and signaling molecules that help create the right environment for stem cells to do their work.
“We found that support cells called fibroadipogenic progenitors were secreting TnC, which made sense given the known role of these during muscle regeneration,” said Sacco.
The researchers then uncovered that tenascin-C communicated with muscle stem cells through a cell receptor called Annexin A2. Cecchini compared this discovery to identifying individual instruments in a musical ensemble, where each contributes to the overall composition. Understanding these different signals from various cell types reveals how they coordinate to repair muscle.
Aging Accelerates the Decline
When the team studied mice lacking tenascin-C, they found fewer muscle stem cells. These cells were also less capable of maintaining their population through self-renewal, resulting in defects in their ability to repair injured muscle. The transplantation experiments confirmed that tenascin-C from the surrounding tissue environment, not just from the stem cells themselves, was essential for proper muscle regeneration.
The connection to aging emerged when the scientists investigated whether tenascin-C levels changed in older mice. They did, substantially. Aged mice had lower levels of the protein, and their muscle stem cells showed reduced ability to migrate to injury sites. This migration defect could be corrected by treating the aged stem cells with tenascin-C in laboratory conditions.
The study demonstrates that exposing aged muscle stem cells to soluble tenascin-C rescues both their ability to migrate and their capacity to maintain a stem cell state. Mice lacking tenascin-C exhibited what researchers describe as a premature aging phenotype, with more severe muscle regeneration problems as they got older.
But tenascin-C presents a delivery challenge for potential therapies. As a large extracellular protein, it doesn’t lend itself to standard drug delivery methods like pills or injections. The research team is now working on potential solutions to overcome what they call this “supersized shipping dilemma.” Developing an effective way to deliver the protein to where it’s needed in aging muscles represents the next major hurdle.
Cecchini emphasized that the overall goal is contributing to greater quality of life as people age. Advances in science, medicine and public health have considerably extended the average lifespan. Now researchers need to make similar improvements to healthspan, beginning by addressing frailty, falls and fractures.
The study was supported by the National Institutes of Health and Association Française contre les Myopathies. Mafalda Loreti, now a principal scientist at Johnson and Johnson and former postdoctoral researcher in the Sacco lab, served as co-first author alongside Cecchini.
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