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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online January 20, 2004 as doi:10.1096/fj.03-0496fje. |
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,2
* Clinic for Gastroenterology, Hepatology and Infectiology,
Department of Physiology,
Department of Anatomy II, Heinrich Heine University Düsseldorf, Germany; and
Medical Clinic I-Cardiology and Pneumology, University Hospital, RWTH Aachen, Germany
3Correspondence: Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Moorenstrasse 5, D-40225 Düsseldorf, Germany. E-mail: haeussin{at}uni-duesseldorf.de
SPECIFIC AIMS
In view of the important role of taurine in muscle physiology and in cell protection against various types of injury, cardiac and skeletal muscle function were examined in the recently generated taurine-deficient mouse model (taut-/-) with a disrupted gene coding for the taurine transporter. The present study identifies taurine transport as a crucial factor for the maintenance of skeletal muscle function and total exercise capacity while cardiac muscle apparently can compensate for the loss of taurine.
PRINCIPAL FINDINGS
1. Taurine tissue levels are strongly decreased in TAUT knockout mice (taut-/- mice)
Deletion of the exon 1 of the taut gene results in an 
98% decrease in heart and skeletal muscle taurine levels.
2. Total exercise capacity is strongly reduced in taut-/- mice
For spiroergometric analysis, wild-type (WT) and taut-/- mice were subjected to treadmill exercise. In contrast to WT mice, which ran up to 20 m/min, taut-/- mice were not able to run faster than 8 m/min at a given angle of 14°. This observation was independent of the age of the mice. X-ray studies revealed no skeletal abnormalities in taut-/- mice.
Experiments designed to determine total exercise capacity at lower speed showed significant differences between WT and taut-/- mice with respect to cumulative running distance. At a treadmill speed of 4 to 8 m/min, the total exercise capacity was decreased by 80% in the taut-/- mice compared with WT controls (Fig. 1
). Similar results were found in treadmill experiments carried out in darkness with dark-adapted mice. However, oxygen consumption (VO2) during the exercise period (i.e. when taut-/- mice were still running) was not significantly different between WT and taut-/- mice. The VCO2/VO2 was increased in taut-/- mice because of increased carbon dioxide production (VCO2). Serum lactate concentration was significantly increased by 57% in exercising taut-/- mice during running. In WT controls the lactate concentration in serum was unaltered under this test condition. Serum creatine kinase levels were doubled in nonexercising taut-/- mice compared with WT mice.
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3. Taurine transporter gene knockout leaves cardiac function uncompromised
In vivo magnetic resonance imaging (MRI) gave no evidence for any anatomical alterations of the heart and showed comparable values for diastolic and systolic volumes as well as cardiac output in taut-/- and WT hearts. Measurements of basal hemodynamic and metabolic parameters of isolated perfused hearts also revealed no significant differences between taut-deficient and WT hearts. Dobutamine stimulation led to a similar increase in left ventricular developed pressure and oxygen consumption in hearts of both groups. In taut-/- hearts the elevated contractility was accompanied by a significantly larger drop (-36.9±9.8 mmHg) in coronary perfusion pressure compared with WT hearts (-16.0±8.3 mmHg). However, the enhanced vasodilation did not result in an increased impairment of cardiac energy state of transgenic hearts as indicated by a similar decrease in phosphocreatine levels in the taut-/- and the WT group during infusion of the drug. Sensitivity to dobutamine stimulation was additionally confirmed by echocardiographic analysis in vivo showing a comparable increase in cardiac output in WT and taut-/- mice as measured with pulsed-wave Doppler.
Since taurine has been suggested to protect against ischemia, an ischemia/reperfusion protocol was applied to perfused hearts in a separate series of experiments. However, neither during the 12 min ischemic period itself nor after 60 min of reperfusion any significant differences in cardiac contractile function and high energy phosphate levels could be observed between WT and taut-/- hearts. Left ventricular end diastolic pressure data indicate comparable recovery from ischemic contracture in both groups.
4. Analysis of taut-/- skeletal muscle revealed electromyographic abnormality
The decreased total exercise capacity was accompanied by an 28% lower conduction velocity in musculus gastrocnemius of taut-/- mice than in WT controls. In contrast, nerve conduction velocity, calculated using time between stimulus in sciatic nerve and onset of the compound action potential in nervus gastrocnemius medialis, was not significantly different between taut-/- and WT mice.
5. Depletion of taurine is compensated by up-regulation of the cytosolic concentration of several organic solutes in heart but not in skeletal muscle
1H nuclear magnetic resonance (NMR) spectroscopy of perchloric acid extracts from taut-/- hearts showed that lack of the taurine transporter led to a nearly complete depletion of the otherwise high cardiac taurine content and induced an up-regulation of the cytosolic concentration of various organic solutes (Fig. 2
). The quantitatively most prominent changes were found for glutamine (+5.1±0.8 mM), alanine (+2.3±0.3 mM), acetate (+1.4±0.2 mM), and glycine (+1.3±0.3 mM). The sum of all measured compounds revealed that in the heart of taut-/- mice the taurine loss was almost fully compensated by the up-regulation of the concentration of other organic solutes.
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Analysis of skeletal muscle extracts also showed severely decreased taurine levels in the transgenic group, but only a minor rise in the content of other osmotically active organic compounds was observed (Fig. 2)
. The sum of the increased levels of glycine (+1.3±0.3 mM), acetate (+0.9±0.2 mM), and lactate (+3.0±1.4 mM) in taut-deficient skeletal muscle did not match the decreased taurine level (-16 mM).
CONCLUSIONS
We have reported that disruption of the taurine transporter (taut) gene in a transgenic mouse model (taut-/-) results in severe plasma hypotaurinemia, a marked impairment of reproduction, retinal degeneration and low levels of taurine in various tissue.
The present study shows that chronically lowered muscle taurine levels affect skeletal but not cardiac muscle function. Lack of the taurine transporter in taut-/- mice results in a reduction of taurine tissue levels by >98% in skeletal and heart muscle compared with control mice. Since taurine deficiency has been implicated as a potential cause of dilated cardiomyopathy in other animal models (fox and cat), it is surprising, that transgenic mice with chronically reduced cardiac taurine levels show a largely normal heart function. In rat heart, pharmacologically-induced taurine depletion led to disordered contractile filaments and clear losses of myofibrillar bundles. In the present study, overall cardiac contractility was unaltered in taut-/- mice. Only vasodilation was enhanced in isolated perfused taut-/- hearts during dobutamine stimulation. While this might indicate that the dobutamine stress is more challenging to taut-deficient hearts, the concentrations of energy-rich phosphates were not different between the two experimental groups. Echocardiography demonstrated a similar sensitivity of WT and taut-/- mice to the dobutamine challenge in vivo. The ischemia reperfusion injury observed in the taut-/- mice was indistinguishable from the WT control. Since taut-/- mice had to cope with taurine deficiency from their early embryonic phase to adulthood, this obviously allowed development of compensatory mechanisms described above. Thus, the cardiac phenotype of taurine depletion may critically depend on whether the effect is acutely induced e.g. by pharmacological means or whether taurine deficiency is chronic such as in taut-/- mice.
In contrast to the heart, skeletal muscle of taut-/- mice shows pronounced abnormalities: a reduced action potential speed and a deficit of more than 10 mM in total organic osmolyte concentration. Morphological abnormalities in taut-/- mice cannot be ruled out: light microscopic analysis of gastrocnemius muscles of 9.5- to 17-month-old male taut-/- and wild-type mice showed a higher number of irregularly appearing muscle fibrils in taut-/- mice. In contrast to these findings but in line with the functional data, no differences in morphology were found on sections of the left cardiac ventricle of these mice. But at present it cannot be excluded that the observed changes of morphology may be due to age dependent structural defects of skeletal muscle found in inbred mice strains. Detailed morphological studies are required to settle these issues. However, it is most likely that changes in taut-/- skeletal muscle account for the decreased overall exercise capacity observed. The increased lactate release during exercise and the elevated serum creatine kinase levels in taut-/- mice provide additional evidence that the reduced performance of these mice is due to a disturbance of normal skeletal muscle function.
In view of the beneficial effects on muscle function via several mechanisms, e.g., excitation-contraction coupling, cytoprotective actions and regulation of the intracellular calcium level, the impaired integrity of taut-/- skeletal muscle may be directly linked to the loss of taurine. On the other hand, impairment of taut-/- skeletal muscle function may be caused by the reduced osmolyte capacity. This disturbed osmolyte balance will result in maladaptation to cell volume changes induced by osmotic, hormonal or oxidative stress or contraction. Impaired cell volume homeostasis will increase the probability of cell dysfunction in taut-/- skeletal muscle. The maintained cardiac function may relate to compensated cardiac osmolyte balance mediated by the up-regulation of several organic solutes. The reason why heart but not skeletal muscle can compensate for the loss of taurine is presently not known. The reduced reproduction of taut-/- mice could have been due to a selection process in which only animals with a compensated cardiac osmolyte balance survived. Disturbance of osmolyte homeostasis in skeletal muscle is obviously not lethal during embryonic development and results in the observed phenotype.
Thus, the present study identifies the taurine transporter as an important factor for the maintenance of exercise capacity as well as for normal skeletal muscle function. It also demonstrates that the heart can compensate for the loss of taurine.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0496fje 
2 These authors contributed equally to this work.
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