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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.

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A Child's Life

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