HIV Drug May Counteract Age-Related Muscle Loss, New Study Finds

Highlights

• Researchers created an atlas of dysfunctional cells that accumulate with age (senescent cells) using gene activity analyses in human muscle tissue.
• Using gene activity analyses, the researchers also identified inflammatory proteins released in muscles from senescent cells during aging.
• Miravaroc, a drug used to treat HIV, disrupts some of these inflammatory proteins by blocking their receptors and rejuvenates muscle in aged mice.

Published in Nature Communications, Wang and colleagues from the Chinese University of Hong Kong demonstrate that the HIV treatment drug maraviroc improves muscle function in aged mice. Moreover, maraviroc significantly reduced cellular senescence (an age-related cellular state where cells stop proliferating and sometimes release inflammatory factors) in the muscle of aged mice. These findings support that maraviroc has the potential to treat sarcopenia, an age-related condition characterized by muscle deterioration and frailty.

The accumulation of senescent cells in tissues throughout the body, including muscle, constitutes a key hallmark of aging. One characteristic associated with senescent cells is the presence of the senescence-associated secretory phenotype (SASP), which encompasses an array of inflammatory molecules. In that regard, some senescent cells emit SASP factors that can induce inflammation in surrounding tissue and even initiate senescence in cells exposed to SASP molecules.

Wang and colleagues focused their research on senescence in skeletal muscle because previous research has shown conflicting reports regarding how senescence affects muscle function. For example, some research has shown that certain senolytics (drugs that selectively eliminate senescent cells), namely, dasatinib and quercetin, increase muscle strength and function in aged mice. On the other hand, other research has suggested that muscle regeneration can occur with pro-senescence therapy, which includes exercise.

These conflicting findings, along with an insufficient understanding of how senescence affects muscle function, propelled Wang and colleagues to analyze senescent cells in skeletal muscle. To do so, the Hong Kong-based researchers aimed to build an atlas of senescent cells based on gene activity. With an atlas of senescent cells in muscle, Wang and colleagues believed they could better understand the role of senescence in aging muscle function, which could aid in identifying interventions against sarcopenia.

An Atlas of Senescent Cells In Human Muscle

To build their atlas of senescent cells in muscle, Wang and colleagues utilized muscle biopsies from the hamstring muscles of 10 male human donors: five young ones (between the ages of 19 and 27) and five older ones (between 60 and 77 years old). Accordingly, Wang and colleagues measured gene activity in cells isolated from the muscle biopsies.

Wang and colleagues’ gene activity analyses unveiled that aged muscle contains lower numbers of muscle stem cells compared to young muscle. This finding suggests that muscle stem cells, crucial for muscle repair and rejuvenation, become depleted as people age.

Next, to confirm increased cellular senescence in aged muscle, Wang and colleagues measured senescence scores based on gene sets associated with senescent cells. These scores suggested elevated senescence in the aged muscle cells compared to young muscle cells.

Identifying a Targetable SASP Factor

To get a better handle on what SASP factors were associated with increased senescence in aged muscle, Wang and colleagues ran a gene activity-based analysis to identify SASP factors expressed in aged muscle cells. Wang and colleagues identified CCR5, a receptor involved in immune responses and inflammation, among SASP factors with increased expression in muscle cells as well as whole muscles. Furthermore, the researchers identified other proteins that bind to CCR5 as having elevated expression levels, also.

This finding led Wang and colleagues to investigate whether miravaroc, known to block the CCR5 receptor, could modify the SASP and alleviate sarcopenia from senescence in mice. For this purpose, Wang and colleagues treated 18-month-old mice (roughly equivalent to 56-year-old humans) with a high dose of maraviroc for three months. Interestingly, this treatment rejuvenated the mice’s muscles, such that they had increased muscle mass. Furthermore, miravaroc-treated mice showed increased grip strength and higher running speed and could even run longer distances.

Because muscle stem cells, crucial for rejuvenating and repairing muscles, were shown to decline in abundance in aged muscle in a previous experiment with human muscle, Wang and colleagues tested maraviroc’s effects on muscle stem cells in mice. Intriguingly, maraviroc increased the abundance of muscle stem cells in aged mice.

The researchers also sought to confirm that, in addition to blocking CCR5, maraviroc lowers the gene activity of multiple SASP factors. Accordingly, Wang and colleagues found that maraviroc indeed reduced SASP gene expression. These findings suggest that maraviroc suppresses the SASP.

To find whether maraviroc rejuvenates muscles of young mice as well, Wang and colleagues treated two-month-old mice (roughly equivalent to 18-year-old humans) with maraviroc. The researchers found no improvements in muscle function or physical capabilities in mice, suggesting that maraviroc’s effects were specific to aged animals.

Developing Other Therapeutics Based On SASP Factors Identified with the Senescent Cell Atlas

With their study, Wang and colleagues generated the first atlas of senescent cells in aged human skeletal muscle. The authors noted that this atlas, with its identification of targetable SASP factors showing increased gene activity, could help with the design or repurposing of therapeutics to counteract age-related muscle inflammation. In this way, researchers could potentially use the atlas to design new drugs or repurpose existing drugs against age-related sarcopenia.

Moreover, the study also used mice to show that the HIV drug, maraviroc, alleviates sarcopenia in aged mice. It is important, though, to point out that human trials will be necessary before anyone can say that maraviroc can confer similar benefits in humans. All the same, with Wang and colleagues’ new atlas of senescent cells in aged human muscle, perhaps researchers can design other drugs that work better than maraviroc against sarcopenia.