- The transcription factor EB (TFEB) regulates the expression of genes that allow muscle cells to use energy.
- The cells in the exercising muscle could not generate enough energy to sustain physical activity when TFEB was knocked out.
- TFEB is sufficient to induce the expression of two major master regulators of mitochondrial biogenesis in muscle, even in the absence of PGC1α and PGC1β, which regulate fat metabolism.
The gene TFEB is a major regulator of muscle function during exercise. Exercise triggers TFEB entering into the nucleus of muscle cells where it regulates the processes that provide energy to the muscle.
These genes include those involved in glucose use, insulin sensitivity and function of the mitochondria, the energy-producer structures inside cells. This work may lead to the design of future treatments for conditions such as diabetes, obesity and metabolic syndrome.
‘TFEB is a major regulator of glucose homeostasis and mitochondrial biogenesis to provide the energetic support to maintain muscle contraction especially during exercise.’
The signaling pathways that control the contraction-mediated beneficial effects on mitochondria and glucose/lipid homeostasis are distinct from insulin signaling and mainly rely on AMPK and PGC1α.
In liver, TFEB regulates genes involved in lipid catabolism, fatty acid oxidation, and ketogenesis. Some of these effects are elicited by TFEB-mediated induction of PGC1α.
In a previous study, the researchers found that TFEB can regulate the response of cells to food deprivation.
"In this study we found that TFEB controls the response of the body to physical exercise," said co-senior author Dr. Andrea Ballabio, professor of molecular and human genetics at Baylor and director of the Telethon Institute of Genetics and Medicine.
"TFEB plays a central role by regulating the expression of genes that allow muscle cells to use energy." TFEB is a transcription factor - a master regulator molecule inside the cell that controls the expression and function of genes.
The scientists studied the role of TFEB in the laboratory mouse. When the researchers knocked out the mouse TFEB gene, the mice had a hard time sustaining exercise.
A closer look inside the cells showed that the mitochondria looked abnormal and were dysfunctional. The cells in the exercising muscle could not generate enough energy to sustain physical activity.
In contrast, when the scientists overexpressed the TFEB gene in mice, the mitochondria looked healthy and increased the amount of energy they normally produced.
The researchers were surprised by these results. "TFEB had not been associated with how cells use energy before," Ballabio said.
"Our discovery of a central pathway that regulates muscle metabolism, use of glucose and mitochondrial function may have important implications in the study of diseases such as obesity and diabetes, as well as in a number of diseases in which muscle function is compromised."
Future studies aimed at identifying drugs that modulate this pathway may lead to the identification of new strategies to treat such diseases.
- Gelsomina Mansueto et al., Transcription Factor EB Controls Metabolic Flexibility during Exercise, Cell Metabolism (2017). http://dx.doi.org/10.1016/j.cmet.2016.11.003.