Tissue environment and chronic exercise both play a key role in shaping skeletal muscle enhancer networks, specifically gene expression, and influences the differentiation and adaption of muscles, according to a Northwestern Medicine study published in PLOS Biology.
Exercise changes the functional properties of muscles, such as enhancing endurance performance or improving insulin sensitivity. However, the molecular regulation that underlies these adaptions, which could help propel efforts in targeting specific pathways for muscle-related conditions or diseases, is not well known, according to Grant Barish, MD, assistant professor of Medicine in the Division of Endocrinology and senior author of the study.
“We still lack a clear picture for the set of regulators that control gene expression in muscle, how they collaborate and which ones are more or less important in conferring training-induced changes,” Barish said.
In the study, Barish and colleagues aimed to define the gene regulatory landscape of different skeletal muscle groups and observe how these landscapes are altered by exercise. The scientists compared exercise training to a genetic model in which mice expressed a gene called perocxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1a), which previous publications have suggested is a central orchestrator of gene changes after exercise.
From a signaling perspective, the scientists found that exercise differs substantially from a single gene perturbation (PGC-1a overexpression) to enhance muscle endurance performance. Specifically, they found that changes in gene regulatory regions between exercise trained mouse models and PGC-1a mouse models showed few similarities. This suggests that different transcription factor pathways are likely to underlie the adaptive changes that occur when muscles are exercised, according to Barish.
“We found that prior studies that have examined gene regulatory regions using skeletal muscle cells in a dish (cell culture) do not resemble the gene regulatory environment in living muscle tissues,” Barish said. “These results highlight the need to study gene regulation within living systems and tissues to gain accurate insights.”
As for next steps, Barish said that further work is still needed to validate the likely transcription factors changing these gene regulatory regions and their specific contributions to the health benefits of exercise.
Krithika Ramachandran, a seventh-year graduate student in the Driskill Graduate Program in Life Sciences, was the first author of the study. This work was funded by National Institutes of Health grants R01DK108987 (GDB) and R01HD089552 (GDB).