ALTERED PYRUVATE-DEHYDROGENASE CONTROL AND MITOCHONDRIAL FREE CA2+ INHEARTS OF CARDIOMYOPATHIC HAMSTERS

The fraction of total pyruvate dehydrogenase in the active, dephosphor ylated form is much lower in the glucose-perfused isolated hearts of t wo myopathic strains of Syrian hamster (BIO 14.6 and TO-2) than in the hearts of healthy control animals (F1B). The myopathic hearts also de velop significantly less pressure under these conditions. Experiments with isolated myocytes from the BIO 14.6 heart reveal that intramitoch ondrial free Ca2+ ([Ca2+]m), a positive effector of pyruvate dehydroge nase interconversion, rises much less in response to a protocol of inc reased frequency of electrical stimulation and adrenergic stimulation than does [Ca2+]m in cells from the healthy control animals (viz from 248 +/- 15 to 348 +/- 44 nM in BIO 14.6 vs. from 241 +/- 35 to 830 +/- 124 nM in FIB, at 4 Hz). As the concentration of Ca2+ that produces h alf-maximal activation of pyruvate dehydrogenase within mitochondria i s 650 nM, this difference between strains is likely the mechanism of t he altered enzyme interconversion. The lesser response of [Ca2+]m to e lectrical stimulation in the BIO 14.6 cells probably results mainly fr om smaller systolic transients in cytosolic free Ca2+ in response to e xcitation of single myocytes from the BIO 14.6 animal. Lowered values of [Ca2+]m within the range described would compromise not only pyruva te dehydrogenase activity, but also flux through the tricarboxylate cy cle in the myopathic heart, owing to the sensitivity of 2-oxoglutarate dehydrogenase to Ca2+. This may explain the decreased activity of oxi dative phosphorylation and performance of work in the myopathic heart.