The MSUD Family Support Group has provided funds to Buck Institute for its preliminary studies investigating metformin , a drug commonly used to treat diabetes, and the impact it may have on the metabolism of branchedchain amino acids (BCAAs) including leucine. They also plan to investigate the use of Triacetoacetin (TAA), a substance which provides molecules which are generated during normal metabolism and which are deficient in individuals with MSUD.
BCAAs play a critical role in the development of
muscle tissue. Leucine is a key trigger for muscle
protein synthesis and is also used as a fuel source
by the muscle, particularly during high intensity
exercise. Abnormalities have been observed in
the muscle fibers of mice with intermediate MSUD
(iMSUD), and have also been observed in critically ill
children with classic MSUD.
As an initial step, the researchers have developed
the tools they will use to demonstrate an effect of
treatment on muscle fiber size and muscle strength.
They have been able to observe that iMSUD mice
have fewer Type 1 “slow twitch” muscle fibers
which are used for endurance types of activity. In
contrast, they found increased levels of Type 2 “fast
twitch” muscle fibers which rely less on oxygen for
their fuel and are used for quick bursts of activity.
But on the whole, the ability of the iMSUD mice
to utilize glucose was diminished, suggesting an
overall physiological defect in MSUD. They also
found that the muscles of iMSUD mice were weaker
than those of mice without MSUD. After treatment
with metformin, iMSUD mice had lower levels of
the keto acid which accumulates when leucine
levels are high, but had similar levels of leucine.
Very encouragingly, treatment with metformin
reversed the loss of Type 1 fibers associated with
the iMSUD mice. And in conjunction, metformin
also restored muscle strength and glucose
physiology of these mice. This suggests a promising
therapeutic outcome for metformin in the future.
The iMSUD mice are short lived with a survival
of about 2-3 weeks. The team is now looking at
the effect of metformin injections on the lifespan
of iMSUD mice. Finally, as the skeletal muscle of
iMSUD mice have insufficient biochemicals used in
aerobic metabolism, the team will also test ways of
supplementing these biochemicals by treatment
with TAA as a precursor drug.
Metformin As A Possible Therapeutic Agent In The Treatment Of MSUD