Taurine is a sulfur-containing amino acid found in very high concentration in skeletal muscle. Taurine deficient mice engineered by knocking out the taurine transporter gene exhibit skeletal muscle wasting, structural defects, and exercise intolerance. In the present study, we investigated the mechanism underlying the development of metabolic abnormalities and exercise intolerance in muscle of the TauTKO phenotype. Running speed and endurance time of TauTKO mice were lower than those of control mice. Blood lactate level was elevated by >3-fold during treadmill running in TauTKO mice but remained largely unaltered by exercise in WT mice. Blood glucose was cleared faster during treadmill running in TauTKO mice than WT mice. AMP-activated kinase (AMPK) β-2 subunit was reduced in TauTKO muscle concomitant with a reduction in α1 and α2 subunits of AMPK. The level of PPARα and its targets, Gpx3, Cpt2, and Echs1, were also decreased in TauTKO muscle. Collectively, taurine depletion impairs metabolic adaptation to exercise in skeletal muscle, a phenomenon associated with a downregulation of AMPK and diminished NADH utilization by the mitochondrial respiratory chain. These findings suggest a crucial role of taurine in regulating energy metabolism in skeletal muscle of exercising TauTKO mice, changes that contribute to impaired exercise endurance. 1. Introduction Taurine, a sulfur-containing amino acid found in very high concentration in mammalian tissues, is particularly high in skeletal muscle. Recent evidence supports a role of taurine in exercise endurance. Mice lacking the taurine transporter (TauT) gene and containing severely reduced muscle taurine content exhibit exercise intolerance in both treadmill and forced swimming tests [1, 2]. Moreover, taurine supplementation prolongs the time to exhaustion during treadmill running, an effect accompanied by the release of intramuscular taurine into the blood [3, 4]. Furthermore, taurine treatment diminishes skeletal muscle cramping in patients with myotonia and liver cirrhosis [5, 6]. However, the mechanism underlying the effect of taurine on exercise endurance has not been clarified. Taurine is considered an essential nutrient in species, such as cat and fox, which exhibit little capacity to synthesize taurine but require large amounts of taurine to maintain normal levels of conjugated bile acids. By comparison, although rodents contain the enzymes for taurine biosynthesis in the liver, maintenance of the large intracellular taurine pool in muscle depends upon uptake of taurine from extracellular space via a
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