A recent study investigated senescence in mouse and human skeletal muscle tissue. The authors demonstrated that the antiviral drug maraviroc reduces senescence and improves muscle health in aged mice [1].
Aging muscle tissue
Senescent cells are one of the hallmarks of aging. One of their key characteristics is the presence of the senescence-associated secretory phenotype (SASP), which includes many pro-inflammatory compounds.
These researchers focused specifically on senescence in skeletal muscles, pointing to previous studies showing conflicting results regarding senescence in muscle function. On one hand, one study showed that treatment with the senolytic drugs dasatinib and quercetin, which selectively kill senescent cells, increased muscle strength and function in aged mice [2]; on the other, a different study suggests that muscle regeneration can be achieved with pro-senescent therapy [3].
Due to such conflicting results and the field’s insufficient understanding in this area, these researchers aimed to build an atlas of senescent cells in skeletal muscle. They believed that this could aid in finding better treatments for sarcopenia, an aging-related disease characterised by a decrease in muscle strength and functioning.
Senescence in muscles
The researcher used biopsies from the hamstring muscles of 10 male donors: five young (19-27 years old) and five aged (60-77 years old), and they measured the gene activity in cells isolated from those biopsies. In their analysis, they only used mononucleated cells prone to senescence and removed the differentiated, post-mitotic myofibers.
Analysis of epigenetics and gene expression divided the cells into 12 clusters of muscle-resident cells. The aged and young cells differed regarding the numbers of cells in clusters, with aged cells showing lower numbers of muscle stem cells among other cell types.
Next, they integrated information from four senescent gene sets (SenMayo, CellAge, GenAge, and Senescence Eigengen) to assess these cells’ senescence score. This score, along with multiple markers of senescence and inflammation, demonstrated increased senescent cell prevalence in four cell types in aged muscle compared to young muscle.
Deeper analysis of SASP dynamics in aging muscle cells identified a subset of SASP factors whose expression was shared among four cell types; however, over 30% of the SASP was cell type-specific. The SASP also impacted many communication pathways in aged muscles, and SASP-mediated interactions were stronger in aged cells than young ones.
Rejuvenating muscles
One of the key components of the SASP, the CCR5 receptor, and the CCL3, CCL4, and CCL5 chemokines that bind to this receptor were significantly elevated in aged muscle stem cells and whole muscles compared to young ones.
This was an important observation as the same group, in a recent study [4], used the CCR5 agonist maraviroc (MVC), an antiviral drug used to treat HIV infection, to reduce inflammation in dystrophic mouse muscles. This prompted them to test maraviroc’s potential senomorphic properties in muscle aging.
First, the researchers tested a high-dose short-term (HDST) treatment regimen, treating 18-month-old mice for 3 months with high doses of maraviroc. This treatment led to rejuvenated and healthier muscles. The researchers observed that maraviroc treatment increased muscle mass and fiber size, reduced inflammation, and improved muscle function, such as increased grip strength, higher running speed, and longer running distance. On the molecular level, the researchers observed an increase in the number of muscle stem cells and a decrease in pro-inflammatory macrophages, decreased levels of cellular senescence, reduced expression of SASP-related genes, and decreased SASP-mediated cellular interaction, all suggesting that maraviroc has senomorphic potential in the treatment of sarcopenia.
Such observations were made only when this regime was applied to aged (18-month-old) but not young (2-month-old) mice, suggesting that maraviroc has aging-specific effects.
Different doses and timing were also tested in aged mice, with low-dose, long-term treatment (6 months) showing positive results, but this was not the case for low-dose, short-term treatment.
Regulating senescence and the SASP
Furthermore, the researchers aimed to understand which transcription factors govern senescence and SASP induction in the muscles of aged humans. They identified many transcription factors (TF), including the known players in senescence and SASP regulation, such as NF-κB1 and C/EBPB. However, they focused on the less-explored transcription factors that belong to the AP-1 family: ATF3 and JUNB.
Through employing many molecular biology techniques, they concluded that ATF3 plays a role in regulating the expression of many genes with senescence-related functions. Their results suggested that genes activated by ATF3 are elevated and genes repressed by ATF3 are downregulated in senescent cells; however, there were differences in the specific upregulated or downregulated genes that depended on cell type.
The second transcription factor, JUNB, did not affect the expression of senescence markers but played a role in SASP. The researchers suggest JUNB can be a “key upstream TF inducer of SASP production.” JUNB expression was increased in aged muscle stem cells derived from mice and human samples, and 54 human SASPs that were regulated by JUNB were also highly expressed in aged mouse muscle stem cells, suggesting a conserved role of JUNB in mice and humans.
Due to the human and mouse similarities, the researchers utilized a mouse model for their subsequent experiments. The expression of the previously mentioned SASP genes was lower in the muscle stem cells isolated from mice with inactivated JUNB, compared to the control. On the other hand, when the researchers overexpressed JUNB in the muscle stem cells of the young mice, the expression of some SASP genes was increased.
Potential therapeutic candidates
This study created the first atlas of senescence in human skeletal muscle. The authors hold that it can help the field better understand the heterogeneous nature of senescence and thus improve the design of relevant therapeutics.
While this study identified maraviroc as a potential good candidate for sarcopenia, there is still a need to test it in humans. The authors also suggest that future studies should “conduct a focused screen for senolytic or senomorphic compounds that target the unique features of senescent cells in skeletal muscle” to identify other potential candidates to treat sarcopenia.
Literature
[1] Li, Y., Li, C., Zhou, Q., Liu, X., Qiao, Y., Xie, T., Sun, H., Ong, M. T., & Wang, H. (2025). Multiomics and cellular senescence profiling of aging human skeletal muscle uncovers Maraviroc as a senotherapeutic approach for sarcopenia. Nature communications, 16(1), 6207.
[2] Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., Inman, C. L., Ogrodnik, M. B., Hachfeld, C. M., Fraser, D. G., Onken, J. L., Johnson, K. O., Verzosa, G. C., Langhi, L. G. P., Weigl, M., Giorgadze, N., LeBrasseur, N. K., Miller, J. D., Jurk, D., Singh, R. J., … Kirkland, J. L. (2018). Senolytics improve physical function and increase lifespan in old age. Nature medicine, 24(8), 1246–1256.
[3] Saito, Y., & Chikenji, T. S. (2021). Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics. Frontiers in pharmacology, 12, 739510.
[4] Li, Y., Li, C., Sun, Q., Liu, X., Chen, F., Cheung, Y., Zhao, Y., Xie, T., Chazaud, B., Sun, H., & Wang, H. (2025). Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis. Nature communications, 16(1), 1324.
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