In vivo effects of myocardial creatine depletion on left ventricular function morphology and lipid metabolism: study in a mouse model.
BACKGROUND
The failing heart is characterized by disturbed myocardial energy metabolism and creatine depletion. The aims of this study were to evaluate in vivo the effects of creatine (Cr) depletion on 1) left ventricular (LV) function, morphology, and lipid metabolism and 2) to test whether functional, morphologic, and metabolic disturbances induced by Cr depletion are reversible.


RESULTS
Male Balb/c mice approximately 20 g were used. Two groups were studied: the mice treated with creatine analogue beta-guanidinopropionic acid (BGP) (n = 30) and controls (n = 30). BGP (1 M) were administered by subcutaneously implanted osmotic minipumps for 4 weeks. The mice were examined in vivo using echocardiography. High-performance liquid chromatography was used for measurements of the myocardial creatine, adenosine nucleotides, and lipids. BGP was discontinued in a subgroup of mice and these animals were followed for an additional 4 weeks, after which echocardiography was performed under resting and stress conditions. Body weight was lower in BGP mice (P < .001) compared with the controls after 4 weeks. The total myocardial Cr pool was approximately 40% lower (P < .001), whereas total nucleotide pool (TAN) was 18% lower (P = n.s.) in the BGP group. LV systolic function was disturbed at rest and stress in the BGP mice (both P < .05). LV dimensions and LV mass were increased in the BGP group (P < .05). There was an accumulation of intracellular triglycerides in the BGP-treated mice (P < .05). Four weeks after BGP discontinuation Cr, TAN and TG content were restored to the normal levels while LV function, dimension, and mass were normalized.


CONCLUSIONS
Myocardial Cr depletion results in LV dysfunction, pathologic remodeling, and lipid accumulation. These alterations are completely reversible on normalization of Cr content. Cr metabolism may be an important target for pharmacologic intervention to increase myocardial efficiency and structural integrity of the failing heart.
Lindbom
Malin
M
Wallenberg Laboratory at Sahlgrenska University, Gothenburg, Sweden.
Ramunddal
Truls
T
Camejo
German
G
Waagstein
Finn
F
Omerovic
Elmir
E
D000818:Animals; D001835:Body Weight; D003401:Creatine / Q000378:metabolism*; D004734:Energy Metabolism; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology; D050356:Lipid Metabolism; D008055:Lipids; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014280:Triglycerides / Q000378:metabolism; D014463:Ultrasonography
D008055:Lipids; D014280:Triglycerides; D003401:Creatine