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Highlights d Skeletal muscle SCOT expression and activity are elevated in obesity d Selective elimination of skeletal muscle SCOT activity improves glycemia in obese mice d Pimozide is a SCOT antagonist that improves glycemia in obese mice d SCOT antagonism within skeletal muscle improves glycemia by increasing PDH activity

FoxO1 inhibition alleviates type 2 diabetes-related diastolic dysfunction by increasing myocardial pyruvate dehydrogenase activity Graphical abstract Highlights d Diabetic cardiomyopathy is characterized by diastolic dysfunction d Genetic and pharmacological inhibition of FoxO1 improves diastolic dysfunction in T2D d FoxO1 inhibition increases myocardial glucose oxidation rates in T2D d FoxO1 inhibition improves diastolic dysfunction in T2D by increasing PDH activity

Barth syndrome (BTHS) is a rare genetic disorder due to mutations in tafazzin that is frequently associated with infantile-onset cardiomyopathy and subsequent heart failure. Although previous studies have provided evidence of perturbed myocardial energy metabolism in BTHS, actual measurements of flux are lacking. We now report a complete energy metabolism profile that quantifies flux in isolated working hearts from a murine model of BTHS, demonstrating that BTHS is associated with a reduction in glucose oxidation.