Salk scientists identify protein BCL6 as a key regulator of muscle maintenance in mice; BCL6-enhancing therapies may prevent muscle loss in GLP-1 users during weight loss.
About one in eight adults in the United States has tried or currently uses a GLP-1 medication, with one-quarter of these individuals citing weight loss as their primary goal. However, weight loss through GLP-1 medications does not differentiate between fat and muscle. Users of these drugs can experience significant muscle loss, which can account for up to 40% of their total weight loss. This raises an important question: how can we achieve weight loss without compromising critical muscle mass?
A new study from the Salk Institute has identified a protein called BCL6 as essential for maintaining healthy muscle mass. Researchers found that mice with lower levels of BCL6 exhibited significantly reduced muscle mass and strength, while increasing BCL6 levels reversed these losses. These findings suggest that combining GLP-1 medications with a drug that boosts BCL6 could help mitigate muscle loss. Such therapies may also benefit other populations at risk of muscle loss, including older adults and patients with systemic conditions like sepsis or cancer.
Insights Into BCL6’s Role in Muscle Maintenance
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.
BCL6: A Critical Player
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?
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.
Therapeutic Potential and Future Research
“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.
Reference: “BCL6 coordinates muscle mass homeostasis with nutritional states” by Hui J. Wang, Weiwei Fan, Sihao Liu, Kyeongkyu Kim, Ayami Matsushima, Satoshi Ogawa, Hyun Gyu Kang, Jonathan Zhu, Gabriela Estepa, Mingxiao He, Lillian Crossley, Christopher Liddle, Minseok S. Kim, Morgan L. Truitt, Ruth T. Yu, Annette R. Atkins, Michael Downes and Ronald M. Evans, 22 January 2025, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2408896122
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.
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2 Comments
“….too much SOCS2 means not enough IFG1, leading to losses in body size and strength.”
“…. so less BCL6 leads to less SOCS2.”
“In animals without BCL6, the lack of control over SOCS2 slowed IGF1 production so much that muscles became weaker and smaller.”
The second quote seems to be contradicted by the third. If quote 2 holds, then removing BCL6 completely should mean SOCS2 is minimally produced (if at all,) which means IGF1 should be unrestricted.
A keen observation! You’ve identified a seeming paradox in the relationship between BCL6, SOCS2, and IGF1. The apparent contradiction arises from context-dependent regulation. BCL6 fine-tunes SOCS2 expression in response to physiological cues. Without BCL6, SOCS2 is dysregulated, leading to reduced IGF1 production, rather than being completely abolished.