Boosting this molecule could help retain muscle while losing fat

Salk News

January 23, 2025

Boosting this molecule could help retain muscle while losing fat

Salk scientists discover protein BCL6 regulates muscle maintenance in mice; BCL6-boosting therapeutics could help GLP-1 users avoid muscle loss while losing weight

January 23, 2025

LA JOLLA-About one in eight adults in the United States has tried or currently uses a GLP-1 medication, and a quarter of those users cite weight loss as their main goal. But weight loss doesn't discriminate between fat and muscle. Patients using GLP-1 drugs can experience rapid and substantial muscle loss, accounting for as much as 40% of their total weight loss. So how can we lose weight without also losing critical muscle?

A new study from the Salk Institute has revealed that a protein called BCL6 is key to maintaining healthy muscle mass. The experiments showed that mice with lower levels of BCL6 had significantly reduced muscle mass and strength, but increasing BCL6 successfully reversed those losses. The results suggest that pairing GLP-1 medications with a BCL6-boosting drug may help counteract unwanted muscle loss. Similar therapies could also be used to treat other populations prone to muscle loss, such as older adults and patients with systemic diseases like sepsis or cancer.

[Link]The stomach sends hunger signals to the brain in the form of ghrelin (blue arrow), prompting the brain to send growth hormone to muscle tissue (pink line). In the foreground, a closer look at the muscle reveals growth hormone (pink orbs) influencing BCL6 (purple blob) to attach to the cell's DNA (purple chain), where it is able to control the production of IGF1.
Click here for a high-resolution image.
Credit: Salk Institute [Link]A cross-section of muscle tissue, showing muscle cells (red) and their nuclei (blue).
Click here for a high-resolution image.
Credit: Salk Institute

The findings were published in Proceedings of the National Academy of Sciences on January 22, 2025.

"Muscle is the most abundant tissue in the human body, so its maintenance is critical to our health and quality of life," says Ronald Evans, professor and director of the Gene Expression Laboratory at Salk. "Our study reveals how our bodies coordinate the upkeep of all this muscle with our nutrition and energy levels, and with this new insight, we can develop therapeutic interventions for patients losing muscle as a side effect of weight loss, age, or illness."

Going too long without eating puts your body in a fasted state. When this happens, your empty stomach sends a hormone called ghrelin to your brain to say, "I'm hungry!" The brain responds by releasing growth hormone into the rest of your body, where it regulates growth and metabolism in your many cells, tissues, and organs. As it travels through your body, growth hormone latches on to cells and directs them to make another protein called insulin-like growth factor 1 (IGF1), which then does the important work of controlling muscle growth.

In the time between growth hormone's arrival and IGF1 synthesis, there is a complex web of proteins that determine how much IGF1 is made. One such protein is SOCS2, which slows down IGF1 production. Without SOCS2, IFG1 production runs out of control and causes gigantism. On the other hand, too much SOCS2 means not enough IFG1, leading to losses in body size and strength.

Still, SOCS2 is only one player in the path between growth hormone and IGF1. To protect people from rapid muscle loss, Salk scientists needed to get a clearer picture of the mechanisms underlying muscle maintenance. In search of other potential players, the researchers scoured a national database of human tissue samples and noticed an abundance of BCL6 in muscle cells-a clue that it may play an important role in this process.

To determine whether BCL6 was involved in muscle maintenance, the team compared mice with and without functional BCL6 proteins. Mice lacking BCL6 had 40% less muscle mass than their healthy counterparts, and the muscle they did have was compromised both in structure and function. However, when the researchers increased the expression of BCL6 in the animals' muscles, this successfully reversed the losses in muscle mass and strength. And when they compared normal mice and those that had fasted overnight, they found fasting mice had less BCL6 in their muscles.

Clearly, BCL6 was controlling muscle maintenance-but how?

[Link]Standing from left: Weiwei Fan, Kyeongkyu Kim, Lillian Crossley, Gabriela Estepa, and Satoshi Ogawa.
Sitting from left: Ronald Evans and Hunter Wang.
Click here for a high-resolution image.
Credit: Salk Institute

Through a series of subsequent experiments, the steps along the path became clear. Fasting promotes the secretion of growth hormone, which reduces BCL6 levels in muscle cells. BCL6 is a regulator of SOCS2, so less BCL6 leads to less SOCS2. At normal levels, this allows BCL6 to control how much SOCS2 is expressed and therefore how much IGF1 is made. In animals without BCL6, the lack of control over SOCS2 slowed IGF1 production so much that muscles became weaker and smaller.

"We are excited to reveal BCL6's important role in maintaining muscle mass," says first author of the study Hunter Wang, a postdoctoral researcher in Evans' lab. "These were very surprising and special findings that open the door for a lot of new discoveries and potential therapeutic innovations."

For GLP-1 patients hoping to lose weight while retaining muscle mass, it's possible that a BCL6-boosting injectable could hit the market one day. In the meantime, the researchers plan to investigate what effects longer-term fasting has on BCL6 and muscle maintenance. Wang also notes that hormones tend to operate in cycles and that BCL6 naturally rises and falls with a strong circadian rhythm. A better understanding of this pattern may help further elucidate BCL6's relationship with growth hormone and muscle growth.

Other authors include Hui Wang, Weiwei Fan, Sihao Liu, Kyeongkyu Kim, Satoshi Ogawa, Hyun Gyu Kang, Jonathan Zhu, Gabreila Estepa, Mingxiao He, Lillian Crossley, Morgan Truitt, Ruth Yu, Annette Atkins, and Michael Downes of Salk; Ayami Matsushima of Kyushu University; Christopher Liddle of University of Sydney; and Minseok Kim of Daegu Gyeongbuk Institute of Science and Technology.

The work was supported by the National Institutes of Health (P01 HL147835, DK057978, DK120515, CCSG P30 CA23100, CCSG P30 CA014195, CCSG P30 CA014195, P30 AG068635), Department of the Navy Office of Naval Research (N00014-16-1-3159), Larry Hillblom Foundation (2021-D-001-NET), Wu Tsai Human Performance Alliance, American Heart Association (916787), Salk GT3 (RRID:SCR_014847) and Waitt Advanced Biophotonics (RRID:SCR_014838) Core Facilities, San Diego Nathan Shock Center, Henry L. Guenther Foundation, and Waitt Foundation.

DOI: 10.1073/pnas.2408896122