Muscle mass plays a crucial role in overall health, strength, and metabolic function, making its regulation essential for maintaining quality of life. A recent study published in the Proceedings of the National Academy of Sciences of the United States of America sheds light on how growth hormone (GH) and the transcriptional regulator BCL6 work together to sustain muscle mass, particularly during fasting.
As Ronald Evans, professor and director of the Gene Expression Laboratory at Salk, explains, “Muscle is the most abundant tissue in the human body, so its maintenance is critical to our health and quality of life. 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.”
Growth hormone is a well-known anabolic hormone responsible for muscle growth and maintenance, primarily through its downstream effector, insulin-like growth factor 1 (IGF1). The study highlights that when GH is present at physiological levels, it effectively sustains muscle mass through the JAK2/STAT5 signaling pathway.
During fasting, GH levels naturally increase, leading to a suppression of BCL6 expression. However, when GH is administered at supraphysiological levels, it further represses BCL6, demonstrating a dose-dependent effect. The study also found that other major fasting-state hormones, such as glucocorticoids, FGF21, and fed-state hormones like insulin and leptin, did not significantly affect BCL6 levels, reinforcing the specificity of GH’s role in regulating this transcription factor.
To explore the functional consequences of BCL6 loss, the researchers generated inducible muscle-specific BCL6 knockout (iBmKO) mice. These mice displayed significant reductions in muscle mass and strength, with a sustained decrease in lean body mass over four months. Importantly, these effects were independent of food intake, suggesting that the loss of BCL6 impairs muscle maintenance directly rather than through changes in appetite. Fast-twitch muscle fibers, which are critical for strength and power, were particularly affected, showing a 40% reduction in mass.
Restoring BCL6 expression in BmKO mice using an adeno-associated virus reversed these deficits, highlighting its essential role in maintaining muscle integrity. The study also demonstrated that pharmacological inhibition of SOCS2 could rescue GH signaling in the absence of BCL6, providing a potential therapeutic target for conditions associated with muscle loss, such as aging, prolonged fasting, or chronic illness.
The identification of BCL6 as a key player in GH signaling suggests that therapies targeting this pathway could help mitigate muscle loss in various conditions. By modulating BCL6 activity, researchers could develop strategies to enhance GH action and preserve muscle mass in patients suffering from cachexia, sarcopenia, or other muscle-wasting disorders.
Sources: Proceedings of the National Academy of Sciences of the United States of America, EurekAlert