When doctors prescribe oxybutynin, it's usually for an unglamorous problem: bladder incontinence. But researchers have discovered a surprising new role for this decades-old drug - one that could open the door to treatments for a devastating class of genetic illnesses known as mitochondrial diseases.
In a paper published Sept. 8 in the American Journal of Physiology-Cell Physiology, a team of Cornell researchers described their finding that the molecule oxybutynin can overcome mitochondrial dysfunction by enhancing cellular glycolysis to improve healthy muscle formation by interacting with a suite of proteins involved in mRNA function.
"Mitochondria are essential for our body to produce energy," said Joeva Barrow, assistant professor of nutritional sciences in the College of Human Ecology who led the study. "If mitochondria are damaged and can no longer produce energy, the cells die, the tissues die and, eventually, the person dies."
Mitochondrial diseases affect about one in every 5,000 people and a large proportion of them are children, Barrow said. Patients often experience profound muscle weakness, neurological decline, heart problems and, in the most severe cases, shortened lives. There are no cures and virtually no effective treatments.
"Our approach was to test a series of small molecules that have never been used to treat mitochondrial disease before," Barrow said. "Previous attempts at small molecules therapy were unsuccessful because of the use of artificial cell systems, but our plan was to use these molecules directly at the source-the muscle stem cells themselves."
After running a screen of thousands of small molecules, they saw oxybutynin emerge as a clear frontrunner. They found that oxybutynin treatment can help muscle stem cells overcome one of the most severe forms of the condition, Complex III mitochondrial dysfunction. Normally, cells rely on mitochondria to generate ATP, the molecule that powers nearly every biological process. In Complex III disorders, that system grinds down, leaving cells starved.
The researchers tested oxybutynin on mouse and human muscle stem cells, the cells responsible for repairing and growing new muscle. These cells, normally stunted by the disease, began multiplying and forming muscle fibers again when treated with the drug.
The effect didn't come from fixing the broken mitochondria. Instead, oxybutynin rewires the cellular energetic pathways to perform glycolysis: the quick-burning process of breaking down glucose. That backup system provided just enough energy to revive growth.
Using a high-tech small molecule binding protein analysis method, the team discovered that oxybutynin binds to proteins involved in RNA processing - the machinery that fine-tunes how cells interpret their genetic code. That interaction set off a cascade of changes, including a boost in amino acid and glucose transport into the cells.
In other words, the drug seems to rewire how diseased muscle cells fuel themselves, finding clever ways to survive without fully functioning mitochondria.
The results held true not only for mouse stem cells but also for human ones. Treated muscle stem cells grew stronger, produced more muscle fibers and maintained higher energy levels than untreated controls.
"Translating these findings to children with mitochondrial disease is happening in real time at Children's Hospital of Philadelphia with collaboration with Dr. Marni Falk," Barrow said. Dr. Marni Falk, is the executive director of the Mitochondrial Medicine Frontier Program at Children's Hospital of Philadelphia. "Their team performs biopsies with kids with mitochondrial diseases, and they are currently testing oxybutynin with those cells."
While this is still far from a clinical therapy - no human patients have yet received oxybutynin for mitochondrial disease - the findings raise hopes that an old, inexpensive drug might be repurposed for a devastating illness. "Oxybutynin already has FDA approval for treatment of bladder disorders" she said.
For families facing mitochondrial disease, even small advances can be a lifeline. Most patients today rely only on supportive care, managing symptoms without any way to slow or reverse the disease.
If further studies confirm its benefits, oxybutynin could speed its way into trials, bypassing years of costly development, Barrow said.
This work was funded by the Hartwell Individual Biomedical Research Award.
