Sarcopenia—reduced muscle mass, strength, and function—is often associated with aging and frequently impacts quality of life in the elderly. Individuals with sarcopenia are also prone to further injury that can lead to drastic health declines.
“It is absolutely crucial that we are able to develop strategies to maintain muscle as we age,” proclaimed Alessandra Sacco, PhD, the dean of the Sanford Burnham Prebys Graduate School of Biomedical Sciences and a professor in the Center for Cardiovascular and Muscular Diseases. “The progressive loss of skeletal muscle mass and function are indicators of poor survival in patients.”
Sacco is the senior author of a new study exploring how the protein composition of muscular extracellular matrix impacts the function of muscular stem cells in the repair and regeneration of muscles during aging.
The paper was published in Communications Biology under the title, “Tenascin-C from the tissue microenvironment promotes muscle stem cell maintenance and function through Annexin A2.”
Prior research out of the Sacco lab explored the prenatal development of muscle cells, exposing the role of tenascin-C (TnC), a large protein found in the extracellular matrix. First co-author Alessandra (Lale) Cecchini, PhD, a scientist in the Sacco lab, shared that “TnC was one of the genes we found that are specifically elevated at the prenatal stage.”
“TnC normally is not really expressed in healthy adult muscle, but it goes up rapidly after an injury to reactivate the programs needed for regeneration and repair,” continued Sacco. “We wanted to understand how TnC influenced stem cells that are primarily responsible for muscle regeneration, and how this relationship was affected by aging.”
To do this, Tenascin-C knockout (TnC-KO) mice were compared to wildtype mice histologically. The TnC-KO mice had fewer muscle stem cells overall, and those present had defects in self-renewal. Further, the mice lacking TnC showed a reduced ability to repair muscular damage compared to controls. “The stem cells also were less able to make new stem cells and maintain an adequate population, and this resulted in defects in their ability to repair injured muscle,” said Cecchini.
The team also identified the source of TnC during regeneration. “We found that support cells called fibroadipogenic progenitors were secreting TnC, which made sense given the known role of these [cells] during muscle regeneration,” Sacco said. Additionally, the team determined that following secretion, TnC acts upon muscle stem cells through a receptor known as Annexin A2.
With these data revealing a clearer understanding of adult function of TnC, the team pursued their initial questions regarding the role of TnC in aging. They found that older mice had lower levels of TnC, and muscle stem cells were also less mobile with increased age, reducing their ability to regenerate at muscle injury sites. However, treating muscle stem cells with TnC corrected these defects.
“We’ve shown that mice lacking TnC exhibit a premature aging phenotype, and that restoring TnC may be a therapeutic strategy for age-related muscle loss,” said Sacco.
While treatment with TnC may be a path to treating sarcopenia, delivery of the extracellular protein presents a challenge. Orally taken or injectable methods may not be the most effective modes of delivery, but the researchers are exploring potential solutions to this problem.
“Advances in science, medicine, and public health have considerably extended the average lifespan,” Sacco pointed out. “Now we need to make the same improvements to the healthspan, beginning by addressing frailty, falls, and fractures.”
“Our overall goal is to contribute to a greater quality of life as we age,” Cecchini concluded.
