Gene’s role in attaining and maintaining muscle mass revealed

• Link to: Northwestern Now Story

• Role in skeletal muscle tissue has been an unknown for decades
• Knocking out gene in utero or in adult mice resulted in 30% loss in muscle mass
• Findings could aid in development of therapeutics for conditions resulting in muscle wasting

CHICAGO --- New research from Northwestern University has uncovered a previously unexplored relationship between a gene critical to immune cells and the establishment and maintenance of skeletal muscle mass and strength in mice.

The BCL6 gene has been known to play a key role in the function of immune cells and the body’s inflammatory response. And for decades, scientists have also known that the gene is expressed heavily in skeletal tissue, but until now, its function in this metabolic tissue was unknown.

“Usually when genes are expressed at high levels, it implies important function,” said lead author Dr. Grant D. Barish. “The study was undertaken with the idea the gene was doing something important in skeletal tissue, but we didn’t know what.”

Barish is the Martha Leland Sherwin Professor of Medicine in the endocrinology division at Northwestern University Feinberg School of Medicine, as well as a practicing clinician. He is an affiliate of the Center for Diabetes and Metabolism and the Simpson Querrey Institute for Epigenetics. He is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Barish has been interested in the BCL6 gene, which encodes a transcription factor, for over a decade, primarily to understand how it can impact diabetes and other endocrine disorders.

The study was published last week (Feb. 9) in the journal Nature Metabolism.

The team used multiple strategies to explore the gene’s function, including deleting the gene in utero to see the impact on pre-formed muscle tissue, and turning off the gene in adult mice, which caused a rapid loss in muscle mass. The mice born without BCL6 genes were runted and developed muscles that were 30% reduced in mass. But interestingly, even post-development, in adult mice, the gene had a strong impact on ability to sustain muscle.

“The findings were totally consistent, and it's a robust effect that suggests a new function for this gene that has principally been studied in the immune system, but it seems to be a very important switch in controlling muscle mass,” Barish said.

When muscle mass falls outside of a normal range, it results from a breakdown of the careful balance the body holds between protein synthesis and degradation. When protein synthesis is affected, typically one step of the protein expression process — transcription or translation — is thrown off balance. But in the case of BCL6, the scientists found a dual function. Using ribosomal sequencing, they found the gene not only controls transcription, but some of its regulated genes that control translation.

The gene additionally seemed to impact degradation of proteins. “There's decreased synthesis occurring, and there's more degradation occurring,” Barish said. “So between the two, the net effect is muscle mass reduction when BCL6 is lost.”

Barish said his study opens up one mechanism to explore in relation to conditions that cause muscle wasting like nerve injuries, nutrient deficiency, cancer and immobility, all conditions that lack medical treatments specific to muscle loss. Cancer and nutritional insufficiency result in reductions of BCL6, but more work needs to come to understand how they impact each other.

Loss of muscle mass is associated with worsening diabetes and insulin resistance, and one of the reasons people get more insulin resistant and more diabetic as they age is they lose muscle mass.

People who lose muscle mass also become weak with aging and more susceptible to falls and fractures that land them with the orthopedist.

Muscle mass has a direct impact on other disease states, quality of life and morbidity and mortality, yet therapeutics for muscle loss do not exist. Barish said there remains much to understand about how muscle mass is controlled on the molecular level that his approaches are beginning to open doors to.

This work was funded by the Veterans Administration (grant I01BX004898), the National Institutes of Health (grants R01DK108987, R56HL158531, R01HL166356-01, R03DK130908-01A1, R01AG078174-01T32 GM008061, HL061322 and NS047726), the Pfizer Aspire award (WI183795) and the Searle Scholar Program (grant SSP-2023-102).