Cardiac hypertrophy and failure are associated with alterations in cardiac substrate metabolism. It remains to be established, however, whether genomically driven changes in cardiac glucose and fatty acid (FA) metabolism represent a key event of the hypertrophic remodeling process. Accordingly, we investigated metabolic gene expression and substrate metabolism during compensatory hypertrophy, in relation to other cardiac remodeling processes. Thereto, cardiac hypertrophy was induced in rats by supra-renal aortic constriction to various degrees, resulting in increased heart/body weight ratios of 22% (Aob-1), 24% (Aob-2) and 32% (Aob-3) (p < 0.005) after 4 weeks. The unaltered ejection fraction in all groups indicated that the hypertrophy was still compensatory in nature. beta-Myosin Heavy Chain protein and ANF mRNA levels were increased in all groups. Only in Aob-3 rats were SERCA2a mRNA levels markedly reduced. In this group, glycolytic capacity was modestly elevated (+ 25%; p < 0.01). Notwithstanding these phenotypical changes, the expression of genes involved in FA metabolism and FA oxidation rate in cardiac homogenates was completely preserved, irrespective of the degree of hypertrophy. These findings indicate that cardiac FA oxidative capacity is preserved during compensatory hypertrophy, and that a decline in metabolic gene expression does not represent a hallmark of the development of hypertrophy.

plays a predominant role in glucose uptake during muscle contraction. In the present study, we have investigated in mice whether disruption of the GLUT-4 gene affects isometric and shortening contractile performance of the dorsal flexor muscle complex in situ. Moreover, we have explored the hypothesis that lack of GLUT-4 enhances muscle fatigability. Isometric performance normalized to muscle mass during a single tetanic contraction did not differ between wild-type (WT) and GLUT-4-deficient [GLUT-4(Ϫ/Ϫ)] mice. Shortening contractions, however, revealed a significant 1.4-fold decrease in peak power per unit mass, most likely caused by the fiber-type transition from fast-glycolytic fibers (IIB) to fast-oxidative fibers (IIA) in GLUT-4(Ϫ/Ϫ) dorsal flexors. In addition, the resting glycogen content was significantly lower (34%) in the dorsal flexor complex of GLUT-4(Ϫ/Ϫ) mice than in WT mice. Moreover, the muscle complex of GLUT-4(Ϫ/Ϫ) mice showed enhanced susceptibility to fatigue, which may be related to the decline in the muscle carbohydrate store. The significant decrease in relative work output during the steady-state phase of the fatigue protocol suggests that energy supply via alternative routes is not capable to compensate fully for the lack of GLUT-4. skeletal muscle; electrical stimulation GLUCOSE IS A major fuel for contracting muscle fibers (6,20). This substrate is supplied to the muscle fiber from extra-and intracellular sources, i.e., blood glucose pool and intracellular glycogen (12,25). The uptake of glucose by skeletal muscle cells is facilitated by a family of membrane-associated glucose transporters (GLUTs; see Refs. 1, 6, and 16). Basal glucose uptake is mediated via the GLUT-1 isoform, whereas the bulk of glucose is primarily transported across the sarcolemma by the insulin-and contraction-regulatable glucose transporter 9,18,24,28,29). After uptake, glucose is metabolized to generate ATP or is stored as glycogen (2). During the initial phase of moderate-intensity exercise, skeletal muscle uses the intracellular glycogen store to meet its energy demand (23). It was recently shown that, during electrical stimulation, blood-borne glucose also serves as a suitable substrate during moderate-intensity exercise in mice (27). To enable detailed studies on the specific role of GLUT-4 in glucose homeostasis in general and in muscle mechanical performance in particular, mice with the GLUT-4 gene disrupted [GLUT-4(Ϫ/Ϫ)] were generated (17,36).Despite the importance of regulatable glucose transporters for muscle energy metabolism, information on the impact of GLUT-4 deficiency on muscle contractile behavior is scarce. It was recently reported that developed isometric tension during in vitro electrical stimulation of isolated extensor digitorum longus (EDL) muscle did not differ between wild-type (WT) and GLUT-4(Ϫ/Ϫ) mice (27). Extrapolation of these findings to the in vivo situation, however, should be done with caution, since the muscle fibers were studied isolated from their natural surroundings, and onl...

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