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Metabolic adaption in Barth syndrome

Metabolic adaption in Barth syndrome
George Schweitzer, PhD, Postdoctoral Research Associate, Washington University School of Medicine, St. Louis, MO

Award—US $50,000 over 1-year period

*Funding for this award was provided by the Will McCurdy Fund for Advancement in Therapies for Barth Syndrome


Individuals with Barth syndrome (BTHS) have altered metabolic functioning arising from a mutation in the tafazzin gene leading to an impairment of the acyltransferase activity in making mature cardiolipin, the most abundant phospholipid in inner-mitochondrial membrane. As an effect, BTHS patients have exercise intolerance and show an excessive reliance on anaerobic metabolism resulting in high blood lactate concentrations at low work rates. Additionally, musculoskeletal abnormalities (such as muscle atrophy and left ventricular dysfunction) and altered plasma amino acid levels described in BTHS patients suggest altered amino acid metabolism. Increased lactate and amino acid metabolism are supportive of enhanced gluconeogenesis to meet energy demand, however this has not yet been evaluated in BTHS patients. In this proposal, the contribution of various metabolic substrates to overall gluconeogenic capacity will be assessed. Specifically, we will examine three metabolic mechanisms known to be upregulated during anaerobic metabolism: [1] the “Cori Cycle”, a metabolic system whereby lactate produced in muscle tissue is delivered to the liver and converted to glucose to be used by muscle, [2] the “Cahill Cycle,” also known as the glucose- alanine cycle, whereby pyruvate is transaminated into alanine in skeletal muscle and delivered to the liver for glucose conversion concomitantly with amine release, and lastly [3] arginine metabolism and incorporation into new glucose will be assessed. We will use stable isotope tracing in the BTHS mouse model and people with BTHS. Experiments performed in mice will help dissect mechanisms of metabolic flux and identify new abnormalities in systemic metabolism. These studies will be complemented with human studies that are already ongoing and will be modified to support these novel analyses. Studies will be conducted at baseline and in the context of endurance exercise, when reliance on these metabolic pathways is enhanced. Understanding these mechanisms and whether BTHS patients are overly reliant on any or all of these adaptive metabolic responses could lead to nutraceutical interventions to enhance their health, quality of life, and may offer patients with BTHS a new way to manage symptoms and progression of the disease.

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