As weight loss medications like Ozempic, classified as GLP-1s, gain popularity, there is a growing scientific focus on how our bodies manage muscle growth. Recent research has identified a protein called BCL6 as essential for maintaining muscle mass. The findings propose that therapies aimed at enhancing BCL6 levels may assist GLP-1 users in preserving their muscle while shedding fat. These treatments could also benefit other groups susceptible to muscle loss, such as the elderly and individuals suffering from conditions like sepsis or cancer.
In the United States, about one in eight adults has used or is currently using a GLP-1 drug, with a quarter of these individuals primarily seeking weight loss. However, weight loss tends to occur in both fat and muscle tissue. Users of GLP-1 medications may face rapid and significant loss of muscle, which can represent up to 40% of their overall weight decrease. The question arises: how can we effectively lose weight without compromising vital muscle?
A recent investigation conducted at the Salk Institute has highlighted that the BCL6 protein is crucial for maintaining proper muscle mass. Experiments on mice demonstrated that those with reduced BCL6 levels experienced notable declines in both muscle mass and strength; however, enhancing BCL6 levels resulted in the restoration of these deficits. This indicates that combining GLP-1 drugs with BCL6-enhancing treatments may mitigate unwanted muscle loss. Similar strategies could also help older adults and patients facing muscle loss due to various systemic diseases.
The study’s conclusions were published in Proceedings of the National Academy of Sciences on January 22, 2025.
“As muscle constitutes the most prevalent tissue in our bodies, its preservation is vital for our overall health and well-being,” states Ronald Evans, the director of the Gene Expression Laboratory at Salk. “Our research sheds light on how our bodies synchronize muscle upkeep with nutritional intake and energy availability, paving the way for therapeutic advancements for those experiencing muscle loss due to weight reduction, aging, or illness.”
When an individual goes extended periods without eating, their body enters a fasted state. This triggers the stomach to release a hormone named ghrelin signaling to the brain, “I need food!” In response, the brain releases growth hormone, which regulates growth and metabolism throughout various cells, tissues, and organs. As growth hormone circulates, it attaches to cells, prompting them to produce another protein known as insulin-like growth factor 1 (IGF1), which plays a crucial role in muscle development.
In the interval between the introduction of growth hormone and the production of IGF1, numerous proteins affect how much IGF1 is generated. One such protein is SOCS2, which inhibits IGF1 synthesis. If SOCS2 levels are too low, IGF1 production can spiral out of control, leading to gigantism. Conversely, with excessive SOCS2, IGF1 levels drop too low, resulting in muscle atrophy and loss of strength.
However, SOCS2 is just one component in the pathway from growth hormone to IGF1. To protect against rapid muscle deterioration, scientists at Salk sought to clarify the mechanisms involved in muscle maintenance. By analyzing a national database of human tissue samples, the researchers discovered a significant presence of BCL6 in muscle cells, suggesting a potential crucial role in muscle preservation.
To investigate BCL6’s role in muscle maintenance, the researchers compared mice with functional BCL6 proteins to those lacking this protein. Mice without BCL6 exhibited a 40% reduction in muscle mass compared to their healthy peers, and the muscle they retained displayed compromised structure and function. When the team augmented BCL6 expression in these mice, it effectively reversed the muscle mass and strength deficits. Furthermore, comparisons between normal mice and those who had fasted overnight revealed that fasting resulted in lower BCL6 levels in muscle cells.
It became evident that BCL6 is a critical regulator of muscle maintenance. But how exactly does it function?
Through subsequent trials, the intricate steps involved began to clarify. Fasting stimulates the release of growth hormone, which in turn decreases BCL6 levels in muscle cells. Since BCL6 regulates SOCS2, diminished BCL6 results in reduced SOCS2. Under regular circumstances, BCL6 can regulate SOCS2 expression, consequently influencing IGF1 production. In animals lacking BCL6, the unregulated SOCS2 production severely hindered IGF1 synthesis, resulting in weaker and smaller muscles.
“We are thrilled to disclose BCL6’s significant role in muscle maintenance,” says Hunter Wang, the study’s lead author and a postdoctoral researcher in Evans’ lab. “These findings are surprising and significant, paving the way for new discoveries and potential therapeutic advancements.”
For GLP-1 users wishing to lose weight while preserving muscle, there may be prospects for a BCL6-enhancing injection in the future. Meanwhile, the researchers plan to explore the long-term effects of fasting on BCL6 and muscle health. Wang also emphasizes that hormones often function cyclically, and BCL6 levels naturally fluctuate in sync with circadian rhythms. Gaining a deeper understanding of this cycle may reveal more about BCL6’s connection with growth hormone and muscle growth.
Other contributors to this research 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 from Salk; Ayami Matsushima of Kyushu University; Christopher Liddle from the University of Sydney; and Minseok Kim from Daegu Gyeongbuk Institute of Science and Technology.
This work received support from various organizations, including the National Institutes of Health (P01 HL147835, DK057978, DK120515, CCSG P30 CA23100, CCSG P30 CA014195, P30 AG068635), the 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), Waitt Advanced Biophotonics (RRID:SCR_014838) Core Facilities, San Diego Nathan Shock Center, Henry L. Guenther Foundation, and Waitt Foundation.
