Metformin reduces toxic acid levels associated with MSUD

Maple Syrup Urine Disease (MSUD) is a rare inherited metabolic disorder involving the dysfunction of an enzyme which breaks down three essential amino acids: leucine, isoleucine and valine.

The only proven treatment for the disease is a liver transplant. Now, researchers at the Buck Institute show that the widely-used diabetes drug, metformin, reduces the toxic acid levels associated with MSUD in both skin cells derived from MSUD patients and in mice. The discovery offers the possibility of a new treatment for a disorder identified 1 in 180,000 births.

In studies, metformin reduced the levels of toxic ketoisocaproic acid (KIC) in patient-derived fibroblasts by 20 to 50 percent and significantly reduced KIC levels in the skeletal muscle of mice bred to have the disease by 69 percent. “We think there is a clear path to a clinical trial and we are hoping that physicians who treat MSUD patients will start pushing in that direction,” said Arvind Ramanathan. “There is a definite need for novel interventions.”

BCAT converts leucine, isoleucine and valine to toxic ketones

Ramanathan came to the MUSD discovery as he was studying various compounds and the enzymes they impact in the context of ageing. Researchers studied the enzyme BCKDH, which is defective in MSUD and also decreases in activity with normal ageing. Ramanathan also studied an enzyme upstream of BCKDH – called BCAT. He says in MSUD, BCAT converts leucine, isoleucine and valine to toxic ketones in the mitochondria of skeletal muscle -resulting in the muscle weakness and atrophy associated with MUSD. “We think the same process may be afoot with age-related sarcopenia and frailty,” he said. “Interestingly, metformin interacts with BCAT and in our MSUD mice treatment with metformin significantly reduced toxic acid buildup in the skeletal muscle.”

“This is a prime example how aging research can have a significant impact on people at any age and the work also highlights the value of studying drugs already approved by the FDA,” said Brian Kennedy, Buck Institute CEO. “In this case, we hope our discovery will help those living with MUSD.”