Retain Muscle, Lose Fat During Weight Loss With BCL6 Protein

Approximately one in eight adults in the United States has used or is currently using a GLP-1 medication, with a quarter of these individuals citing weight loss as their primary goal. However, weight loss from these drugs doesn’t differentiate between fat and muscle. Users may experience rapid and significant muscle loss, which can account for up to 40% of their total weight loss(1^✔ ✔Trusted Source
BCL6 coordinates muscle mass homeostasis with nutritional states

Go to source). So, how can we lose weight while preserving essential muscle mass?

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BCL6 Protein: A New Key to Preserving Muscle Mass and Combating Muscle Loss

A recent study from the Salk Institute has identified a protein called BCL6 as critical for maintaining healthy muscle mass. In experiments, mice with reduced levels of BCL6 showed significantly lower muscle mass and strength, while boosting BCL6 levels effectively reversed these losses. These findings suggest that combining GLP-1 medications with a BCL6-enhancing drug could help prevent muscle loss. Similar therapies might also benefit other groups prone to muscle loss, including older adults and patients with systemic diseases like sepsis or cancer.

The findings were published in Proceedings of the National Academy of Sciences.

“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.

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Muscle Maintenance: The Role of SOCS2 and BCL6 in IGF1 Regulation

In the time between the 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.

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BCL6: A Key Regulator of Muscle Mass and Strength Through IGF1 Control

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.

BCL6 Discovery Sparks Hope for Muscle-Preserving Therapies

“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 opened 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:

1. BCL6 coordinates muscle mass homeostasis with nutritional states - (https://www.pnas.org/doi/10.1073/pnas.2408896122)

Source-Eurekalert